Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use

ABSTRACT

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection. Thus, in one specific aspect the invention relates to formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (IX).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application of InternationalApplication No. PCT/EP11/62949, filed Jul. 27, 2011, which claims thebenefit of priority of European Patent Application Nos. EP 10171342.8,filed Jul. 29, 2010, EP 11160738.8, filed Mar. 31, 2011, EP 11160731.3,filed Mar. 31, 2011, and EP 11160728.9, filed Mar. 31, 2011, all ofwhich are incorporated herein by reference.

The invention relates to (hetero)aryl cyclopropylamine compounds,particularly the compounds of formula (I), (Ia), (Ib), (II) or (III) asdescribed and defined herein, and their use in therapy, including e.g.,in the treatment or prevention of cancer, a neurological disease orcondition, or a viral infection.

Aberrant gene expression in affected tissue as compared to normal tissueis a common characteristic of many human diseases. This is true forcancer and many neurological diseases which are characterized by changesin gene expression patterns. Gene expression patterns are controlled atmultiple levels in the cell. Control of gene expression can occurthrough modifications of DNA: DNA promoter methylation is associatedwith suppression of gene expression. Several inhibitors of DNAmethylation are approved for clinical use including the blockbusterVidaza™. Another class of modifications involve histones which form theprotein scaffold that DNA is normally associated with (coiled around) ineukaryotic cells. Histones play a crucial role in organizing DNA and theregulated coiling and uncoiling of DNA around the histones is criticalin controlling gene expression—coiled DNA is typically not accessiblefor gene transcription. A number of histone modification have beendiscovered including histone acetylation, histone lysine methylation,histone arginine methylation, histone ubiquinylation, and histonesumoylation, many of which modify accessibility to the associated DNA bythe cells transcriptional machinery. These histone marks serve torecruit various protein complexes involved in transcription andrepression. An increasing number of studies are painting an intricatepicture of how various combinations of histone marks control geneexpression in cell-type specific manner and a new term has been coinedto capture this concept: the histone code.

The prototypical histone mark is histone acetylation. Histone acetyltransferase and histone deacetylases are the catalytic machines involvedin modulation of this histone mark although typically these enzymes areparts of multiprotein complexes containing other proteins involved inreading and modifying histone marks. The components of these proteincomplexes are typically cell type and typically comprise transcriptionalregulators, repressors, co-reppresors, receptors associated with geneexpression modulation (e.g., estrogen or androgen receptor). Histonedeacetylase inhibitors alter the histone acetylation profile ofchromatin. Accordingly, histone deacetylase inhibitors like SAHA, TSA,and many others have been shown to alter gene expression in various invitro and in vivo animal models. Clinically, histone deacetylaseinhibitor have demonstrated activity in the cancer setting and are beinginvestigated for oncology indications as well as for neurologicalconditions and other diseases.

Another modification that is involved in regulating gene expression ishistone methylation including lysine and arginine methylation. Themethylation status of histone lysines has recently been shown to beimportant in dynamically regulating gene expression.

A group of enzymes known as histone lysine methyl transferases andhistone lysine demethylases are involved in histone lysinemodifications. One particular human histone lysine demethylase enzymecalled Lysine Specific Demethylase-1 (LSD1) was recently discovered (Shiet al. (2004) Cell 119:941) to be involved in this crucial histonemodification. LSD1 has a fair degree of structural similarity, and aminoacid identity/homology to polyamine oxidases and monoamine oxidases, allof which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amineoxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/ornitrogen carbon bonds.

Several groups have reported LSD1 inhibitors in the literature. Shaunaet al. recently reported a new series of urea and thiourea analogs basedon an earlier series of polyamines which were shown to inhibit LSD1 andmodulate histone methylation and gene expression in cells ((2010) J.Med. Chem. PMID: 20568780). Sharma et al. note that “To date, only a fewexisting compounds have been shown to inhibit LSD1.” Some efforts weremade to make analogs of the histone peptide that is methylated by theenzyme, other efforts have focused on more small molecule like moleculesbased on known MAO inhibitors.

Cyclopropylamine containing compounds are known to inhibit a number ofmedically important targets including amine oxidases like MonoamineOxidase A (MAO-A; or MAOA), Monoamine Oxidase B (MAO-B; or MAOB), andLysine Specific Demethylase-1 (LSD1). Tranylcypromine (also known as2-phenylcyclopropylamine), which is the active ingredient of Parnate®and one of the best known examples of a cyclopropylamine, is known toinhibit all of these enzymes.

Gooden et al. reported trans-2-arylcyclopropylamine analogues thatinhibit LSD1 with Ki values is the range of 188-566 micromolar (Goodenet al. ((2008) Bioorg. Med. Chem. Let. 18:3047-3051)). Most of thesecompounds were more potent against MAO-A as compared to MAO-B. Ueda etal. ((2009) J. Am. Chem. Soc. 131(48):17536-17537) reportedcyclopropylamine analogs selective for LSD1 over MAO-A and MAO-B thatwere designed based on reported X-ray crystal structures of theseenzymes with a phenylcyclopropylamine-FAD adduct and a FAD-N-propargyllysine peptide. The reported IC50 value for phenylcyclopropylamine wasabout 32 micromolar for LSD1 whereas compounds 1 and 2 had values of 2.5and 1.9 micromolar respectively.

Mimasu et al. disclose a series of phenylcyclopropylamine derivativeshaving benzoyl substitutions at the ortho-position (2010) BiochemistryPMID: 20568732. Ortho-substituted compounds from this series without abenzoyl group in the ortho-position e.g., phenyl, alkoxy, or having acombination of ortho- and para-substitution appeared to be less potentinhibitors of LSD1 than those compounds having benzoyl substituents inthe ortho-position. The most active compounds from this series had abenzoyl group at the ortho-position and one or two meta-fluorosubstitutions: biphenyls like S1310 and compounds having large groups inthe para-position were less effective LSD1 inhibitors.

The phenylcyclopropylamines have been the subject of many studiesdesigned to elucidate a SAR for MAO inhibition. Kaiser et al. ((1962) J.Med. Chem. 5:1243-1265); Zirkle et al. ((1962) J. Med. Chem. 1265-1284;U.S. Pat. Nos. 3,365,458; 3,471,522; 3,532,749) have disclosed thesynthesis and activity of a number of phenylcyclopropylamine relatedcompounds. Other phenylcyclopropylamine type compounds are disclosed inBolesov et al. ((1974) Zhurnal Organicheskoi Khimii 10:8 1661-1669) andRussian Patent No. 230169 (19681030).

Studies have been conducted with phenylcyclopropylamine relatedcompounds to determine selectivity for MAO-A versus MAO-B since MAO-Ainhibitors can cause dangerous side-effects (see e.g., Yoshida et al.(2004) Bioorg. Med. Chem. 12(10):2645-2652; Hruschka et al. (2008) BiorgMed. Chem. (16):7148-7166; Folks et al. (1983) J. Clin. Psychopharmacol.(3)249; and Youdim et al. (1983) Mod. Probl. Pharmacopsychiatry(19):63).

Binda et al. examined a series of phenylcyclopropylamine derivatives inrelation to their inhibitory activity against LSD1 and LSD2 as well asexamining stereochemical issues in relation to the cyclopropyl ring (J.Am. Chem. Soc. (2010) May 19; 132(19):6827-33). Binda et al. reportedthat their para substituted phenylcyclopropylamine derivatives arenon-selective which as a group are appear to be better MAO-A inhibitorsthan MAO-B inhibitors. Furthermore, their inhibitory activities againstMAO-A and LSD1 were roughly the same.

Substituted cyclopropylamines can be chiral. Chiral compounds are oftencharacterized by their ability to rotate plane polarized light and aretypically referred to as (+) or (−) depending on the direction theyrotate the light. Another nomenclature is the d- and l- which are shortfor dextrorotatory and levorotatory. R and S designation are used tospecify absolute configurations since the ability of chiral molecules torotate plane polarized light, e.g., the direction of rotation, does notcorrelate always with absolute configurations.

Tranylcypromine has two stereocenters corresponding to the carbons ofthe cyclopropyl ring that bear the amino substituent and the phenylsubstituent. Theoretically, a compound having the phenylcyclopropylaminestructure of tranylcypromine can have four stereochemicalconfigurations: two corresponding to the cis (1S,2S or 1R,2R) and twocorresponding to the trans (1S,2R or 1R,2S). Tranylcypromine correspondsto the trans isomer of 2-phenylcyclopropylamine and is a racemate of the(−) and (+) enantiomers (i.e., a 50:50 mixture of the 1S,2R and 1R,2Senantiomers) and, thus, is optically inactive.

The (−) enantiomer of tranylcypromine was synthesized, characterized,and absolute configuration determined. Riley et al. (1972) J. Med. Chem.15(11):1187-1188. The (−) stereoisomer was determined to have the 1R,2Sabsolute configuration by synthesis from1R,2R-2-phenylcyclopropanecarboxylic acid. Later studies using othertechniques confirmed this assignment (Binda et al. (2010) JACS132:6827-6833) by determination of the X-ray structure of the para-bromoderivative of a stereoisomer of 2-phenylcyclopropylamine and comparisonto the CD spectra of the tranylcypromine stereoisomers. These resultswere confirmed by stereoselective synthesis of the enantiomers oftranylcypromine.

It is reported that the (+) isomer (1S,2R) oftrans-2-phenylcyclopropylamine is more potent against MAO than the (−)isomer (1R,2S) (Riley et al. (1972) J. Med. Chem. 15(11):1187-1188)using an in vivo tryptamine convulsion model (Zirkie et al. (1962) J.Med. Pharm. Chem. 5:1265).

Binda et al. reported a significant difference in the ability of thestereoisomers of tranylcypromine to inhibit MAO-B with the (+)stereoisomer being much more potent using in vitro biochemical assays.The (−) stereoisomer (1R,2S) was a slightly stronger inhibitor of LSD1than the (+) stereoisomer (Ki of 168 uM versus a Ki of 284 uM) but thesedifferences were considered marginal by the authors (Binda et al.((2010) JACS 132:6827-6833 see page 6828).

Recently, a group reported another investigation of the stereoisomers oftranylcypromine with LSD1 (Benelkebir et al. (2011) Bioorg Med.Chem.doi: 10.1016/j.bmc.2011.02.017). They found that the stereoisomersof tranylcypromine were about equipotent for LSD1: Ki(inact) for the (+)stereoisomer was of 26.6 uM, 28.1 uM for the (−) stereoisomer and 25.0uM for the racemate.

Another group studying the effect of the stereochemical configurationaround the cyclopropylamine group of substituted2-phenylcyclopropylamine compounds reported the stereoisomer having the(1S,2R) absolute configuration (as determined by NMR using chiral shiftreagents) was a more potent LSD1 inhibitor as compared to itsenantiomer, both in in vitro biochemical assays and cell based growthinhibition assays in Hela and HEK293, whereas the enantiomers behavedequally in the neuroblastoma line, SH—SY5Y (Ogasawara et al. (2011)Bioorg. Med. Chem. Doi:10.1016/j.bmc. 2010.12.024).

Given the differences in assays/experimental protocols used in thedifferent studies referenced above, it is difficult to compare resultsbetween studies. Regardless, it is not clear from these data howderivatives or analogs of compounds having a phenylcyclopropylamine corecan be optimized to provide potent inhibitors of LSD1, and LSD1 andMAO-B, based on the stereochemical configuration of the carbons of thecyclopropyl moiety. Furthermore, it is not clear from these studies howthe selectivity of N-substituted aryl- and hetero-cyclopropylaminecompounds for both LSD1 and MAO-B can be modulated to provide compoundsthat inhibit these enzymes to a greater extent than MAO-A. Suchcompounds are expected to have beneficial safety windows by avoidingMAOA inhibition and the so-called “cheese effect”.

In view of the lack of adequate treatments for conditions such as cancerand neurodegeneration, there is a desperate need for disease modifyingdrugs and drugs that work by inhibiting novel targets. There is a needfor the development of better LSD1 selective inhibitors particularlythose which selectively inhibit LSD1 or LSD1 in combination with MAO-B.

SUMMARY OF THE INVENTION

The present invention relates to the identification of compounds andtheir use in treating or preventing diseases. The invention provides(hetero)cyclopropylamine compounds, including the compounds of Formula(I), (II) or (III) as described and defined herein. The presentinvention particularly provides a compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof, pharmaceuticalcompositions comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier, and their uses for treating diseases. One use of the compoundof Formula (I) is for treating or preventing cancer. Another use for thecompound of Formula (I) is to inhibit LSD1. The present invention thusrelates to a compound of Formula (I) or an enantiomer, a diastereomer,or a mixture thereof, or a pharmaceutically acceptable salt or solvatethereof for use in treating or preventing cancer. Thus, the inventionprovides a compound of Formula (I), or a pharmaceutically acceptablesalt or solvate thereof, and further relates to its use in treating orpreventing human disease.

Accordingly, the present invention provides a compound of Formula (I) ora pharmaceutically acceptable salt or solvate thereof:

(A) is a cyclyl group having n substituents (R3).(B) is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclylgroup or the cyclyl moiety comprised in said -(L1)-cyclyl group has nsubstituents (R2).(L1) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene.(D) is a heteroaryl group or an -(L2)-heteroaryl group, wherein saidheteroaryl group or the heteroaryl moiety comprised in said-(L2)-heteroaryl group has one substituent (R1), and further whereinsaid heteroaryl group is covalently bonded to the remainder of themolecule through a ring carbon atom or the heteroaryl moiety comprisedin said -(L2)-heteroaryl group is covalently bonded to the (L2) moietythrough a ring carbon atom.(L2) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene.(R1) is a hydrogen bonding group.Each (R2) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea.

Each (R3) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea.

n is independently 0, 1, 2, 3 or 4.

The substituents of the cyclopropyl moiety, i.e., the group (A) and thegroup —NH—CH₂-(D), are preferably in the trans-configuration.

In a related aspect, the invention provides a pharmaceutical compositioncomprising a compound of Formula (I) or an enantiomer, a diastereomer,or a mixture thereof, or a pharmaceutically acceptable salt or solvatethereof as defined above and a pharmaceutically acceptable carrier.Preferred embodiments of the compound of Formula (I), e.g., for use inthe composition of the invention are defined and described herein belowin more detail.

In another aspect, the invention provides a method of treating orpreventing a disease or condition comprising administering, to a patient(preferably a human) in need of treatment or prevention, atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of Formula (I) as described above or as in theembodiments thereof as described below, or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier. This aspect canbe reformulated as a compound of Formula (I) as defined above in thefirst aspect of the invention for use as a medicine. In a relatedaspect, the invention provides a pharmaceutical composition for use intreating or preventing a disease or condition wherein said compositioncomprises a therapeutically effective amount of a compound of Formula(I) sufficient for treating or preventing said disease or condition. Ina more specific embodiment, the invention provides a compound of Formula(I) for use in the treatment of a disease associated with LSD1.

In yet another aspect, the invention provides a method of inhibitingLSD1 activity comprising administering, to a patient in need oftreatment, a therapeutically effective amount of a compositioncomprising a compound of Formula (I) or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier sufficient toinhibit LSD1 activity. Preferably the patient is a human. This aspectcan be reformulated as a compound of Formula (I) as herein defined foruse as a LSD1 inhibitor. In a related aspect, a method for treating anindividual is provided, said method comprising identifying an individualin need of treatment and administering to said individual atherapeutically effective amount of a compound of Formula (I). In apreferred aspect, the therapeutically effective amount of a compound ofFormula (I) is an amount sufficient to inhibit LSD1. Preferredembodiments of the compounds of Formula (I) for use in the compositionand method of this aspect of the invention are as described in moredetail herein.

In again another aspect, the invention provides a method of treating orpreventing cancer comprising administering, to a patient in need oftreatment or prevention, a therapeutically effective amount of acomposition comprising a compound of Formula (I) as defined above or asthe embodiments described in more detail herein, and a pharmaceuticallyacceptable carrier. This aspect can be reformulated as a compound ofFormula (I) as defined above in the first aspect of the invention foruse in the treatment or prevention of cancer. In a related aspect, theinvention provides a pharmaceutical composition for use in treating orpreventing cancer wherein said composition comprises a therapeuticallyeffective amount of a compound of Formula (I) sufficient for treating orpreventing cancer. In another related aspect, the invention provides acompound of Formula (I) or a pharmaceutical composition for thetreatment or prevention of a cancer wherein said cancer is chosen frombreast cancer, lung cancer, prostate cancer, colorectal cancer, braincancer, skin cancer, blood cancer (e.g., leukemia, including, forexample, acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),or hairy cell leukemia), lymphoma and myeloma. Said compositionpreferably comprises a therapeutically effective amount of a compound ofFormula (I) sufficient for treating or preventing said cancer. In apreferred aspect, the therapeutically effective amount of a compound ofFormula (I) is an amount sufficient to inhibit LSD1. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-4 methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-9 methylation levels.

In again another aspect, the invention provides a method of treating orpreventing a neurological disease or condition comprising administering,to a patient in need of treatment or prevention, a therapeuticallyeffective amount of a composition comprising a compound of Formula (I)as defined above or in the embodiments described in more detail herein,and a pharmaceutically acceptable carrier. This aspect can bereformulated as a compound of Formula (I) as defined above for use inthe treatment or prevention of a neurological condition or disease. In arelated aspect, the invention provides a pharmaceutical composition foruse in treating or preventing a neurological condition or diseasewherein said composition preferably comprises a therapeuticallyeffective amount of a compound of Formula (I) sufficient for treating orpreventing said neurological disease or condition. In another relatedaspect, the invention provides a compound of Formula (I) or apharmaceutical composition for the treatment or prevention of aneurological disease or condition wherein said neurological disease orcondition is chosen from depression, Alzheimer's disease, Huntingtondisease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Dementiawith Lewy Bodies, or Frontotemporal Dementia, particularly fromdepression, Alzheimer's disease, Huntington disease, Parkinson'sdisease, or Dementia with Lewy Bodies. Said composition preferablycomprises a therapeutically effective amount of a compound of Formula(I) sufficient for treating or preventing said disease or condition. Ina preferred aspect, the therapeutically effective amount of a compoundof Formula (I) is an amount sufficient to inhibit LSD1. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-4 methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-4 methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-9 methylation levels.

In still another aspect, the invention provides a method for identifyinga compound which is a selective inhibitor of LSD1, the method comprisingselecting or providing a compound of Formula (I) as defined herein, anddetermining the ability of the compound to inhibit LSD1 and MAO-A and/orMAO-B, wherein a compound that inhibits LSD1 to a greater extent thanMAO-A and/or MAO-B is identified as a LSD1 selective inhibitor. Thecompound of this aspect that is an LSD1 inhibitor can be used to treatdisease, particularly human disease.

In still another aspect, the invention provides a method for identifyinga compound which is a dual inhibitor of LSD1 and MAO-B, the methodcomprising selecting or providing a compound of Formula (I) as definedherein, and determining the ability of the compound to inhibit LSD1,MAO-A, and MAO-B, wherein a compound that inhibits LSD1 and MAO-B to agreater extent than MAO-A is identified as a LSD1 MAO-B dual inhibitor.The compound of this aspect that is an LSD1 MAO-B inhibitor can be usedto treat disease, particularly human disease.

Thus, in one embodiment of the invention, the pharmaceutical compositioncomprising a LSD1 selective inhibitor of Formula (I), or apharmaceutically acceptable salt or solvate thereof is useful fortreating and/or preventing a disease in an individual. In one aspect, atherapeutically effective amount of the composition is administered toan individual in an amount sufficient to prevent or treat a disease. Ina more specific aspect, the disease is cancer. In an even more specificaspect, the disease is a cancer chosen from prostate, brain, colorectal,lung, breast, skin, and blood cancer. In one specific aspect, the canceris prostate cancer. In one specific aspect, the cancer is lung cancer.In one specific aspect, the cancer is brain cancer. In one specificaspect, the cancer is blood cancer (e.g., leukemia, including, forexample, acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),or hairy cell leukemia). In one specific aspect, the cancer is breastcancer. In one specific aspect, the cancer is colorectal cancer. In onespecific aspect, the cancer is lymphoma. In one specific aspect, thecancer is myeloma. In another preferred aspect, the therapeuticallyeffective amount is an amount sufficient to inhibit LSD1. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-4 methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-9 methylation levels.

Furthermore, the inventors unexpectedly found that the stereochemicalconfiguration of the cyclopropyl carbons of N-substitutedarylcyclopropylamine compounds substantially affects the potency of LSD1inhibition, MAO-B inhibition and MAO-A inhibition. The inventors haveshown that the (−) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineis about 20-fold more potent against LSD1 than the corresponding (+)stereoisomer. Furthermore, the (−) stereoisomer retained substantialMAO-B inhibitory activity. Notably, the selectivity for LSD1/MAO-A forthe (−)/(+) stereoisomer was over 100 fold as judged by k_(inact)/K_(I)values. Thus, (−) stereoisomers of N-substituted(hetero)arylcyclopropylamine compounds are unexpectedly potent andselective LSD1 inhibitors compared to their respective enantiomers.Furthermore, the compounds of the invention have improved selectivityagainst MAO-A, preferentially inhibiting MAO-B and LSD1. The inventiontherefore relates to optically active (hetero)arylcyclopropylaminecompounds, in particular optically active N-substituted aryl- orheteroaryl-cyclopropylamines, and their use for treating or preventing adisease or a disorder.

Thus, in one specific aspect the invention relates to a substantiallypure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine (e.g., a compound of Formula (II) or (III)as described and defined herein below) for use in a method of treatingor preventing a disease or disorder. Desirably, the disease or disorderis one that is treatable or preventable by LSD1 inhibition, LSD1inhibition and MAO-B inhibition, or MAO-B inhibition. In a specificaspect, a substantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 90% or greater (−) stereoisomer and10% or less (+) stereoisomer. In a more specific aspect, a substantiallypure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 95% or greater (−) stereoisomer and5% or less (+) stereoisomer. In yet a more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 98% or greater (−) stereoisomer and2% or less (+) stereoisomer. In an even more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 99% or greater (−) stereoisomer and1% or less (+) stereoisomer. In yet an even more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 99.5% or greater (−) stereoisomerand 0.5% or less (+) stereoisomer. In one embodiment, theabove-described percentages refer to mole-%. The substantially purestereoisomer of an N-substituted aryl- or heteroaryl-cyclopropylamine,in one aspect, is for use in a method of treating or preventing cancer,depression, a neurodegenerative disease or disorder, or a viralinfection.

Furthermore, in another aspect, the invention is a compositioncomprising a stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine (e.g., a compound of Formula (II) or (III)as described and defined herein below) wherein said composition has a90% or more enantiomeric excess of the (−) stereoisomer of theN-substituted aryl- or heteroaryl-cyclopropylamine. In a specific aspectsaid composition has a 95% or more enantiomeric excess of the (−)stereoisomer of the N-substituted aryl- or heteroaryl-cyclopropylamine.In a more specific aspect said composition has a 98% or moreenantiomeric excess of the (−) stereoisomer of the N-substituted aryl-or heteroaryl-cyclopropylamine. In an even more specific aspect saidcomposition has a 99% or more enantiomeric excess of the (−)stereoisomer of the N-substituted aryl- or heteroaryl-cyclopropylamine.The composition in one aspect of the invention is for use in a method oftreating or preventing cancer, depression, a neurodegenerative diseaseor disorder, or a viral infection.

Furthermore, in another aspect, the invention is a pharmaceuticalcomposition comprising a stereoisomer of an N-substituted aryl- orheteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III)as described and defined herein below) and a pharmaceutically acceptablecarrier wherein said composition has a 90% or more enantiomeric excessof the (−) stereoisomer of the N-substituted aryl- orheteroaryl-cyclopropylamine. In a specific aspect said composition has a95% or more enantiomeric excess of the (−) stereoisomer of theN-substituted aryl- or heteroaryl-cyclopropylamine. In a specific aspectsaid composition has a 99% or more enantiomeric excess of the (−)stereoisomer of the N-substituted aryl- or heteroaryl-cyclopropylamine.The pharmaceutical composition of this paragraph is for use in a methodof treating or preventing cancer, depression, a neurodegenerativedisease or disorder, or a viral infection.

In one aspect of the invention, the optically active N-substituted aryl-or heteroaryl-cyclopropylamine or pharmaceutically acceptable salt orsolvate thereof, for use in a method of treating or preventing a diseaseor disorder, as described herein, is of Formula (II):R1^(II)-(A^(II))-R2^(II)  (II)wherein:(A^(II)) is an aryl or heteroaryl group having 2 substituents, R1^(II)and R2^(II), and 1, 2, or 3 optional substituents wherein said optionalsubstituents are independently chosen from halo, C₁-C₃ alkyl, or C₁-C₃alkoxy;R1^(II) is an -(L₁ ^(II))-(R3^(II)) group;R3^(II) is an aryl or heteroaryl group having 1, 2, 3, 4, or 5 optionalsubstituents independently chosen from halo, —OH, —NHSO₂R^(A), alkyl,alkoxy, cyano, —CF₃, or —OCF₃, wherein R^(A) is a C₁-C₆ alkyl or phenyl;L₁ ^(II) is chosen from a bond, —CH₂O—, —CH₂CH₂O—, —OCH₂—, —OCH₂CH₂—,—CH₂CH₂—, —CH₂—, —CH₂CH₂CH₂—, or —O—;R2^(II) is -Cyclopropyl-NH-(L₂ ^(II))-(R4^(II)) wherein said cyclopropylgroup has two chiral centers substituted in the trans orientationcorresponding to the carbons to which (A) and —NH-(L₂ ^(II))-(R4^(II))are covalently attached;R4^(II) is a 5 or 6 membered heteroaryl ring having 1, 2, or 3 optionalsubstituents chosen from alkyl, —NHR^(B), —OR^(B), or halo wherein R^(B)is hydrogen, C₁-C₃ alkyl, or —C(═O)CH₃;L₂ ^(II) is a branched or unbranched C₁-C₄ alkylene groupand wherein said compound of Formula (II) is optically active.

The invention also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder. Preferably, the disease ordisorder is mediated through an amine oxidase. In one aspect, the amineoxidase is LSD1 or MAO-B.

Furthermore, the inventors found a subset of optically active compoundsof Formula (II) as shown in Formula (III) which are inhibitors of LSD1or of LSD1 and MAO-B.

The invention thus further relates to an optically active compound ofFormula (III) or a pharmaceutically acceptable salt or solvate thereof:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is an aryl or heteroaryl group having 2 substituents, R1^(III)and R2^(III) and 1, 2, or 3 optional substituents independently chosenfrom halo, C₁-C₃ alkyl, or C₁-C₃ alkoxy;R1^(III) is an -(L₁ ^(III))-(R3^(III)) group;R3^(III) is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2,3, 4, or 5 optional substituents independently chosen from halo, —OH,—NHSO₂R^(A), alkyl, alkoxy, cyano, or —OCF₃, wherein R^(A) is a C₁-C₆alkyl or phenyl;L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;R2^(III) is -Cyclopropyl-NH-(L₂ ^(III))-(R4^(III)) wherein saidcyclopropyl group has two chiral centers substituted in the transorientation corresponding to the carbons to which (A^(III)) and —NH-(L₂^(III))-(R4^(III)) are covalently attached;R4^(III) is a 5-membered heteroaryl ring having 1, 2, or 3 optionalsubstituents wherein said optional substituents are independently chosenfrom —NH₂ or —NH(C₁-C₃) alkyl;L₂ ^(III) is —CH₂— or —CH₂CH₂—;and wherein said compound of Formula (III) is optically active.

Additionally, the invention is a pharmaceutical composition comprisingan optically active N-substituted aryl- or heteroaryl-cyclopropylamineof Formula (II) or (III) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

The invention also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine ofFormula (II) or (III) as defined above, or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier, foruse in treating or preventing a disease or disorder.

In one aspect, the invention is a method of treating or preventing adisease or disorder comprising administering, to an individual in needof treatment, a therapeutically effective amount of an optically activeN-substituted aryl- or heteroaryl-cyclopropylamine, particularly acompound of Formula (II) or (III), or a pharmaceutically acceptable saltor solvate thereof. In a more specific aspect, the disease or disorderis human disease or disorder chosen from cancer, depression, aneurodegenerative disease or disorder, or a viral infection. In oneaspect, the neurodegenerative disease or disorder is Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis,Frontotemporal Dementia, or Dementia with Lewy Bodies.

In one aspect, the invention is a method of treating or preventing adisease or disorder comprising identifying an individual in need oftreating or preventing and administering to said individual atherapeutically effective amount of an optically active N-substitutedaryl- or heteroaryl-cyclopropylamine, particularly a compound of Formula(II) or (III), or a pharmaceutically acceptable salt or solvate thereof.In a more specific aspect, the disease or disorder is human disease ordisorder chosen from cancer, depression, a neurodegenerative disease ordisorder, or a viral infection. In one aspect, the neurodegenerativedisease or disorder is Huntington disease, Parkinson disease, Alzheimerdisease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, orDementia with Lewy Bodies.

In one aspect, the invention provides a method for enriching anenantiomer of a trans N-substituted cyclopropylamine (particularly of acompound of Formula (II) or (III), or of a compound of Formula (I)wherein the substituents on the cyclopropyl moiety are intrans-orientation), the method comprising:

Contacting a trans-substituted cyclopropylamine with a chiralrecrystallization agent in a solvent (particularly under conditions thatare sufficient for the crystallization of the salt of the chiralrecrystallization agent and the trans substituted cylopropylamine); andisolating the crystallized salt of the chiral recrystallization agentand the trans substituted cyclopropylamine. In one aspect, the transcyclopropylamine is an N-substituted aryl- orheteroaryl-cylopropylamine. In one aspect, the trans cyclopropylamine is4 benzoxy-2-phenylcyclopropylamine or a derivative thereof wherein theamine is protected with a protecting group.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the identification of compounds andtheir use in treating and preventing diseases. The present inventionprovides compounds of Formula (I), pharmaceutical compositionscomprising a compound of Formula (I) or a pharmaceutically acceptablesalt or solvate thereof and a pharmaceutically acceptable carrier, andtheir use for treating diseases. One use of the compounds of Formula (I)is for treating cancer. The compounds of Formula (I) can be used as LSD1selective inhibitors that inhibit LSD1 to a greater extent than MAO-Aand MAO-B or as LSD1/MAO-B dual inhibitors that inhibit LSD1 and MAO-Bto a greater extent than MAO-A. The compounds of Formula (I) asdescribed herein are generally better inhibitors of LSD1 by a factor ofmore than 10 to 20 or more as compared to tranylcypromine, with improvedselectivity against MAO-A. Thus, these compounds are LSD1 selective inthat they inhibit LSD1 to an extent greater than MAO-A and MAO-B or areLSD1/MAO-B duals inhibitors that inhibit LSD1 and MAO-B to a greaterextent than MAO-A.

The present invention provides a compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof:

(A) is a cyclyl group having n substituents (R3). Preferably, (A) is anaryl group or a heteroaryl group, wherein said aryl group or saidheteroaryl group has n substituents (R3). More preferably, (A) isphenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolyl, wherein(A) has n substituents (R3). Even more preferably, (A) is phenyl orpyridyl, wherein said phenyl or said pyridyl has n substituents (R3). Inone embodiment, (A) has 0 or 1 substituent (R3). In a furtherembodiment, (A) has 0 substituents (R3). In a further embodiment, (A)has 1 substituent (R3). It is to be understood that, if n is 0, thecyclyl group is not substituted with any substituents (R3) but mayinstead be substituted with hydrogen.(B) is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclylgroup or the cyclyl moiety comprised in said -(L1)-cyclyl group has nsubstituents (R2). Said cyclyl group or the cyclyl moiety comprised insaid -(L1)-cyclyl group may, for example, be an aryl group (e.g.,phenyl, naphthyl or anthracenyl) or a heteroaryl group (e.g., pyridinyl,thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, orpyrimidinyl). Preferably, (B) is —O—CH₂-phenyl or phenyl, wherein (B)has n substituents (R2). In one embodiment, (B) is phenyl having nsubstituents (R2). In a further embodiment, (B) is —O—CH₂-phenyl havingn substituents (R2). In one embodiment, (B) has 0, 1 or 2 substituents(R2). In a further embodiment, (B) has 0 or 1 substituent (R2). In afurther embodiment, (B) has 0 substituents (R2). In a furtherembodiment, (B) has 1 substituent (R2).(L1) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene. Said alkylenemay, e.g., be a straight-chain or branched chain alkylene having from 1to 6 carbon atoms. Said heteroalkylene may, e.g., be a straight-chain orbranched chain alkylene having from 1 to 6 carbon atoms, wherein 1, 2(if present) or 3 (if present) carbon atoms are each replaced by aheteroatom selected independently from O, N or S; accordingly, saidheteroalkylene may, e.g., be a straight-chain or branched chain alkylenehaving from 1 to 4 carbon atoms, wherein 1 or 2 non-adjacent carbonatoms are each replaced by O.(D) is a heteroaryl group or a -(L2)-heteroaryl group, wherein saidheteroaryl group or the heteroaryl moiety comprised in said-(L2)-heteroaryl group has one substituent (R1), and further whereinsaid heteroaryl group is covalently bonded to the remainder of themolecule through a ring carbon atom or the heteroaryl moiety comprisedin said -(L2)-heteroaryl group is covalently bonded to the (L2) moietythrough a ring carbon atom. Preferably, (D) is thiazolyl, oxadiazolyl,oxazolyl, isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl,pyridinyl or pyrimidinyl, wherein said thiazolyl, oxadiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinylor pyrimidinyl has one substituent (R1). In particular, (D) may bethiazolyl, oxadiazolyl or pyrimidinyl, wherein said thiazolyl, saidoxadiazolyl or said pyrimidinyl has one substituent (R1). Mostpreferably, (D) is oxadiazolyl.(L2) is —O—, —NH—, —N(alkyl)-, alkylene or heteroalkylene. Said alkylenemay, e.g., be a straight-chain or branched chain alkylene having from 1to 6 carbon atoms. Said heteroalkylene may, e.g., be a straight-chain orbranched chain alkylene having from 1 to 6 carbon atoms, wherein 1, 2(if present) or 3 (if present) carbon atoms are each replaced by aheteroatom selected independently from O, N or S; accordingly, saidheteroalkylene may, e.g., be a straight-chain or branched chain alkylenehaving from 1 to 4 carbon atoms, wherein 1 or 2 non-adjacent carbonatoms are each replaced by O.(R1) is a hydrogen bonding group. For example, (R1) may be —OH,—O(alkyl), —NH₂, —NH(alkyl) (e.g., —NHCH₃), —N(alkyl)(alkyl) (e.g.,—N(CH₃)₂), amido, —SO—NH₂, —SO—NH(alkyl), —SO—N(alkyl)(alkyl),—S(O)₂NH₂, —S(O)₂NH(alkyl), —S(O)₂N(alkyl)(alkyl), —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)(alkyl), -alkylene-C(═O)NH₂ (e.g.,—CH₂—C(═O)NH₂), -alkylene-C(═O)NH(alkyl) (e.g., —CH₂—C(═O)NH(alkyl)),-alkylene-C(═O)N(alkyl)(alkyl) (e.g., —CH₂—C(═O)N(alkyl)(alkyl)),—NHC(═O)-alkyl (e.g., —NHC(═O)CH₃), —N(alkyl)-C(═O)-alkyl (e.g.,—N(—CH₃)—C(═O)CH₃), -alkylene-NH₂ (e.g., —CH₂—NH₂), -alkylene-NH(alkyl),or -alkylene-N(alkyl)(alkyl), wherein it is preferred that theaforementioned alkyl and alkylene groups each independently have from 1to 6 carbon atoms. Preferably, (R1) is —OH, —NH₂, amido, —S(O)₂NH₂,—C(═O)NH₂, —CH₂—C(═O)NH₂, —NHC(═O)CH₃, —NHCH₃, —N(CH₃)₂ or —CH₂—NH₂,particularly —OH, —NH₂, —NHCH₃, amido, —S(O)₂NH₂, —C(═O)NH₂,—CH₂—C(═O)NH₂, or —CH₂—NH₂. More preferably, (R1) is —NH₂ or —NHCH₃.Even more preferably, (R1) is —NH₂.Each (R2) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea. For example, each (R2) may beindependently selected from hydroxyl, halo (e.g., —Cl or —F) orhaloalkyl (e.g., —CF₃). Accordingly, each (R2) may, for example, beselected independently from hydroxyl or haloalkyl (e.g., —CF₃). It ispreferred that each (R2) is halo, more preferably —F.Each (R3) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate, or urea. For example, each (R3) may beindependently selected from alkyl, cyclyl, amino, amido, alkylamino,hydroxyl, halo, haloalkyl, haloalkoxy, cyano, sulfonamide, alkoxy, acyl,carboxyl, carbamate, or urea.n is independently 0, 1, 2, 3 or 4. For example, each n may beindependently 0, 1 or 2. In particular, each n may be independently 0 or1.

The substituents of the cyclopropyl moiety, i.e., the (A) group and the—NH—CH₂-(D) group, are preferably in trans-configuration.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I) wherein (A) is an aryl or heterocyclyl. In amore preferred embodiment (A) is phenyl, pyridinyl, thiophenyl,pyrrolyl, furanyl, or thiazolyl. In an even more preferred embodiment(A) is phenyl or pyridinyl.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I) wherein, (B) is a -L2-cyclyl. In a morepreferred embodiment (B) is —O-phenyl or —O—CH₂-phenyl. In an even morepreferred embodiment (B) is —O—CH₂-phenyl. In one specific embodimentthe phenyl group of said (B) group has 1, 2, 3, or 4 optionalsubstituents (R2) independently chosen from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I) wherein, (B) is cyclyl. In a more preferredembodiment (B) is phenyl. In one specific embodiment, the phenyl groupof said (B) group has 1, 2, 3, or 4 optional substituents (R2)independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido,C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy,cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl,carbamate or urea.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I), wherein (R2) is hydroxyl, halo or haloalkyl.In one preferred embodiment (R2) is —OH or —CF₃. In another preferredembodiment (R2) is fluoro or chloro.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I), wherein (D) is a monocyclic heteroaryl. In amore preferred embodiment (D) is thiazolyl, oxadiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinylor pyrimidinyl. In one specific embodiment, said cyclyl (D) has onesubstituent (R1).

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (I) wherein (R1) is a hydrogen bonding group. Forexample, (R1) may be —OH, —O(alkyl), —NH₂, —NH(alkyl) (e.g., —NHCH₃),—N(alkyl)(alkyl), amido, —SO—NH₂, —SO—NH(alkyl), —SO—N(alkyl)(alkyl),—S(O)₂NH₂, —S(O)₂NH(alkyl), —S(O)₂N(alkyl)(alkyl), —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)(alkyl), -alkylene-C(═O)NH₂ (e.g.,—CH₂—C(═O)NH₂), -alkylene-C(═O)NH(alkyl) (e.g., —CH₂—C(═O)NH(alkyl)),-alkylene-C(═O)N(alkyl)(alkyl) (e.g., —CH₂—C(═O)N(alkyl)(alkyl)),—NHC(═O)-alkyl (e.g., —NHC(═O)CH₃), —N(alkyl)-C(═O)-alkyl (e.g.,—N(—CH₃)—C(═O)CH₃), -alkylene-NH₂ (e.g., —CH₂—NH₂), -alkylene-NH(alkyl),or -alkylene-N(alkyl)(alkyl), wherein it is preferred that theaforementioned alkyl and alkylene groups each independently have from 1to 6 carbon atoms. In a more preferred embodiment (R1) is a —NH₂, —OH,amido, —NHC(═O)CH₃, —NHCH₃ or —S(O)₂NH₂. In an even more preferredembodiment (R1) is —NH₂.

The compound of Formula (I) as described and defined herein may, forexample, be a compound of the following Formula (Ia) or apharmaceutically acceptable salt or solvate thereof:

wherein (A), (B), (D), (R1), (R2), (R3) and n have the meanings or thepreferred meanings described herein for the compound of Formula (I).

Preferably, the compounds of the invention, including in particular thecompounds of Formula (I), (Ia) or (Ib) as described herein, are used totreat a disease in a mammal and more preferably a human. Morepreferably, the human disease is chosen from cancer (e.g., breastcancer, lung cancer, prostate cancer, colorectal cancer, brain cancer,skin cancer, blood cancer (e.g., leukemia, including, for example, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronicneutrophilic leukemia, chronic eosinophilic leukemia, chroniclymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairycell leukemia), lymphoma, or myeloma), a neurological condition ordisease (e.g., depression, Alzheimer's disease, Huntington disease,Parkinson's disease, Amyotrophic Lateral Sclerosis, FrontotemporalDementia, or Dementia with Lewy Bodies), or a viral infection.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia) wherein (A) is aryl or heterocyclyl. In amore preferred embodiment (A) is phenyl, pyridinyl, thiophenyl,pyrrolyl, furanyl, and thiazolyl. In an even more preferred embodiment(A) is a phenyl or a pyridinyl.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia) wherein (B) is -L2-cyclyl. In a morepreferred embodiment (B) is —O-phenyl or —O—CH₂-phenyl. In an even morepreferred embodiment (B) is —O—CH₂-phenyl. In one specific embodimentthe phenyl group of said (B) group has 1, 2, 3, or 4 optionalsubstituents (R2) independently chosen from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia) wherein (B) is cyclyl. In a more preferredembodiment (B) is phenyl. In one specific embodiment the phenyl group ofsaid (B) group has 1, 2, 3, or 4 optional substituents (R2)independently chosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido,C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy,cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl,carbamate or urea.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia) wherein (R2) is hydroxyl, halo or haloalkyl.In one preferred embodiment (R2) is —OH or —CF₃. In another preferredembodiment (R2) is fluoro or chloro.

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia), wherein (D) is a monocyclic heteroaryl. In amore preferred embodiment (D) is thiazolyl, oxadiazolyl, oxazolyl,isoxazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinylor pyrimidinyl. In one specific embodiment said cyclyl (D) has onesubstituent (R1).

In one preferred embodiment of the first aspect, the invention providesa compound of Formula (Ia) wherein (R1) is a hydrogen bonding group. Forexample, (R1) may be —OH, —O(alkyl), —NH₂, —NH(alkyl) (e.g., —NHCH₃),—N(alkyl)(alkyl), amido, —SO—NH₂, —SO—NH(alkyl), —SO—N(alkyl)(alkyl),—S(O)₂NH₂, —S(O)₂NH(alkyl), —S(O)₂N(alkyl)(alkyl), —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)(alkyl), -alkylene-C(═O)NH₂ (e.g.,—CH₂—C(═O)NH₂), -alkylene-C(═O)NH(alkyl) (e.g., —CH₂—C(═O)NH(alkyl)),-alkylene-C(═O)N(alkyl)(alkyl) (e.g., —CH₂—C(═O)N(alkyl)(alkyl)),—NHC(═O)-alkyl (e.g., —NHC(═O)CH₃), —N(alkyl)-C(═O)-alkyl (e.g.,—N(—CH₃)—C(═O)CH₃), -alkylene-NH₂ (e.g., —CH₂—NH₂), -alkylene-NH(alkyl),or -alkylene-N(alkyl)(alkyl), wherein it is preferred that theaforementioned alkyl and alkylene groups each independently have from 1to 6 carbon atoms. In a more preferred embodiment (R1) is a —NH₂, —OH,amido, —NHC(═O)CH₃, —NHCH₃ or —S(O)₂NH₂. In a more preferred embodiment(R1) is a —NH₂, —OH, amido, or —S(O)₂NH₂. In an even more preferredembodiment (R1) is —NH₂.

Thus in a preferred aspect, the invention provides a compound of Formula(Ib) or a pharmaceutically acceptable salt or solvate thereof or its usein treating or preventing a disease or disorder:

wherein:(A) is a phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, or thiazolylgroup having n optional substituents (R3);(B) is —O—CH₂-phenyl or phenyl, wherein the phenyl group has n optionalsubstituents (R2);(D) is thiazolyl, oxadiazolyl or pyrimidinyl wherein said (D) has onesubstituent (R1);(R1) is —NH₂, —OH, amido, —NHC(═O)CH₃, —NHCH₃ or —S(O)₂NH₂;each (R2) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl,amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl,haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl,carboxyl, carbamate or urea;each (R3) is independently chosen from alkyl, alkenyl, alkynyl, cyclyl,amino, amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl,haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl,carboxyl, carbamate, or urea; andn is independently 1, 2, 3 or 4.

In one embodiment of this aspect, the compound of Formula (Ib) is usedto treat a disease in a mammal and more preferably a human. In anotherembodiment, the disease or disorder is chosen from cancer, aneurological condition or disease, or a viral infection. In oneembodiment, the neurological disease or disorder is Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, orFrontotemporal Dementia.

In another embodiment of this aspect, the disease or disorder is cancer.In another embodiment the cancer is prostate cancer. In another specificembodiment of this aspect the cancer is breast cancer. In another yetspecific embodiment of this aspect the cancer is lung cancer. In anotheryet specific embodiment of this aspect the cancer is colorectal cancer.In another yet specific embodiment of this aspect the cancer is braincancer. In another yet specific embodiment of this aspect the cancer isskin cancer. In another yet specific embodiment of this aspect thecancer is blood cancer (e.g., leukemia, including, for example, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronicneutrophilic leukemia, chronic eosinophilic leukemia, chroniclymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairycell leukemia), a lymphoma, or myeloma.

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (A) is aryl or heterocyclyl. In a more preferredembodiment (A) is phenyl, pyridinyl, thiophenyl, pyrrolyl, furanyl, orthiazolyl. In an even more preferred embodiment (A) is phenyl orpyridinyl.

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (B) is -L2-cyclyl. In a more preferred embodiment (B)is —O-phenyl or —O—CH₂-phenyl. In an even more preferred embodiment (B)is —O—CH₂-phenyl. In one specific embodiment the phenyl group of said(B) group has 1, 2, 3, or 4 optional substituents (R2) independentlychosen from alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido,alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano,sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl, carboxyl, carbamate orurea.

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (B) is cyclyl. In a more preferred embodiment (B) isphenyl. In one specific embodiment the phenyl group of said (B) grouphas 1, 2, 3, or 4 optional substituents (R2) independently chosen fromalkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino,hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl,sulfonamide, alkoxy, acyl, carboxyl, carbamate or urea.

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (R2) is hydroxyl, halo or haloalkyl. In one preferredembodiment (R2) is —OH or —CF₃. In another preferred embodiment (R2) isfluoro or chloro.

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (D) is a monocyclic heteroaryl. In a more preferredembodiment (D) is thiazolyl, oxadiazolyl, oxazolyl, isoxazolyl,thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl, pyridinyl orpyrimidinyl. In one specific embodiment said cyclyl (D) has onesubstituent (R1).

In another specific embodiment of this aspect, the invention provides acompound of Formula (Ib) for use in treating or preventing a disease ordisorder wherein (R1) is a hydrogen bonding group. For example, (R1) maybe —OH, —O(alkyl), —NH₂, —NH(alkyl) (e.g., —NHCH₃), —N(alkyl)(alkyl),amido, —SO—NH₂, —SO—NH(alkyl), —SO—N(alkyl)(alkyl), —S(O)₂NH₂,—S(O)₂NH(alkyl), —S(O)₂N(alkyl)(alkyl), —C(═O)NH₂, —C(═O)NH(alkyl),—C(═O)N(alkyl)(alkyl), -alkylene-C(═O)NH₂ (e.g., —CH₂—C(═O)NH₂),-alkylene-C(═O)NH(alkyl) (e.g., —CH₂—C(═O)NH(alkyl)),-alkylene-C(═O)N(alkyl)(alkyl) (e.g., —CH₂—C(═O)N(alkyl)(alkyl)),—NHC(═O)-alkyl (e.g., —NHC(═O)CH₃), —N(alkyl)-C(═O)-alkyl (e.g.,—N(—CH₃)—C(═O)CH₃), -alkylene-NH₂ (e.g., —CH₂—NH₂), -alkylene-NH(alkyl),or -alkylene-N(alkyl)(alkyl), wherein it is preferred that theaforementioned alkyl and alkylene groups each independently have from 1to 6 carbon atoms. In a more preferred embodiment (R1) is —NH₂, —OH,amido, —NHC(═O)CH₃, —NHCH₃ or —S(O)₂NH₂. In an even more preferredembodiment (R1) is —NH₂.

In one aspect, the invention provides a stereoisomer or a mixturethereof, of a compound of Formula (I), (Ia) or (Ib).

In another aspect, the invention relates to a derivative or analog of acompound of Formula (I), (Ia) or (Ib).

In yet another aspect, the invention relates to a solvate or polymorphof a compound of Formula (I), (Ia) or (Ib).

In yet another aspect, the invention relates to a prodrug of a compoundof Formula (I), (Ia) or (Ib).

In yet another aspect, the invention relates to a metabolite of acompound of Formula (I), (Ia) or (Ib).

In another aspect, the invention provides a method of treating orpreventing a disease or condition comprising administering, to a patient(preferable human) in need of treatment or prevention, a therapeuticallyeffective amount of a pharmaceutical composition comprising a compoundof Formula (I), (Ia) or (Ib) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier. This aspect can be reformulated as a compound of Formula (I),(Ia) or (Ib) for use as a medicine. In a related aspect, the inventionprovides a pharmaceutical composition for use in treating or preventinga disease or condition wherein said composition comprises atherapeutically effective amount of a compound of Formula (I), (Ia) or(Ib) sufficient for treating or preventing said disease or condition. Ina more specific embodiment the invention provides a compound of Formula(I), (Ia) or (Ib) for use in the treatment of a disease associated withLSD1. In another preferred aspect, the therapeutically effective amountis an amount sufficient to modulate histone methylation levels. Inanother preferred aspect, the therapeutically effective amount of acompound of Formula (I), (Ia) or (Ib) is an amount sufficient tomodulate the level of histone-3 lysine-4 methylation. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone-3 lysine-9 methylation levels.

In yet another aspect, the invention provides a pharmaceuticalcomposition comprising a compound of Formula (I), (Ia) or (Ib) and apharmaceutically acceptable carrier. In a more specific aspect, thepharmaceutical composition comprises a therapeutically effective amountof a compound of Formula (I), (Ia) or (Ib). In an even more specificaspect, the therapeutically effective amount of a compound of Formula(I), (Ia) or (Ib) is an amount effective to inhibit LSD1. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone methylation levels. In another preferredaspect, the therapeutically effective amount of a compound of Formula(I), (Ia) or (Ib) is an amount sufficient to modulate the level ofhistone 3 lysine 4 methylation. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-9 methylation levels.

In again another aspect, the invention provides a method of inhibitingLSD1 activity comprising administering, to a patient in need oftreatment, a therapeutically effective amount of a compositioncomprising a compound of Formula (I), (Ia) or (Ib) or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier sufficient to inhibit LSD1 activity. This aspect can bereformulated as a compound of Formula (I), (Ia) or (Ib) as hereindefined for use as a LSD1 inhibitor. This aspect can also bereformulated as a compound of Formula (I), (Ia) or (Ib) for themanufacture of a medicament for the treatment of a disease associated toLSD1. In a related aspect, a method for treating an individual isprovided, said method comprising identifying an individual in need oftreatment and administering to said individual a therapeuticallyeffective amount of a compound of Formula (I), (Ia) or (Ib). In apreferred aspect, the therapeutically effective amount of a compound ofFormula (I), (Ia) or (Ib) is an amount sufficient to inhibit LSD1.

In another preferred aspect, the therapeutically effective amount is anamount sufficient to modulate histone methylation levels. In anotherpreferred aspect, the therapeutically effective amount of a compound ofFormula (I), (Ia) or (Ib) is an amount sufficient to modulate the levelof histone 4 lysine 3 methylation. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-9 methylation levels.

Preferred embodiments of the compounds of Formula (I), (Ia) or (Ib) foruse in the composition and method of this four aspect of the inventionare as defined herein above in the first aspect of the invention.

In still another aspect, the invention provides a method of treating orpreventing cancer comprising administering, to a patient in need oftreatment, a therapeutically effective amount of a compositioncomprising a compound of Formula (I), (Ia) or (Ib) as defined above inthe first aspect of the invention, and a pharmaceutically acceptablecarrier. This aspect can be reformulated as a compound of Formula (I),(Ia) or (Ib) as defined above in the first aspect of the invention foruse in the treatment or prevention of cancer. In a related aspect, theinvention provides a pharmaceutical composition for use in treating orpreventing cancer wherein said composition comprises a therapeuticallyeffective amount of a compound of Formula (I), (Ia) or (Ib) sufficientfor treating or preventing cancer. In another related aspect, theinvention provides a compound of Formula (I), (Ia) or (Ib) or apharmaceutical composition for the treatment or prevention of a cancerwherein said cancer is chosen from testicular cancer, breast cancer,lung cancer, prostate cancer, colorectal cancer, brain cancer, skincancer, blood cancer (e.g., leukemia, including, for example, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronicneutrophilic leukemia, chronic eosinophilic leukemia, chroniclymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairycell leukemia), lymphoma and myeloma, wherein said composition comprisesa therapeutically effective amount of a compound of Formula (I), (Ia) or(Ib) sufficient for treating or preventing the said cancer. In apreferred aspect, the therapeutically effective amount of a compound ofFormula (I), (Ia) or (Ib) is an amount sufficient to inhibit LSD1. Inanother preferred aspect, the therapeutically effective amount is anamount sufficient to modulate histone methylation levels. In anotherpreferred aspect, the therapeutically effective amount of a compound ofFormula (I), (Ia) or (Ib) is an amount sufficient to modulate the levelof histone-3 lysine-4 methylation. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-9 methylation levels.

In still another aspect, the invention provides a method of treating orpreventing a neurological disease or disorder comprising administering,to a patient in need of treatment or prevention, a therapeuticallyeffective amount of a composition comprising a compound of Formula (I),(Ia) or (Ib) as defined above in the first aspect of the invention, anda pharmaceutically acceptable carrier. This aspect can be reformulatedas a compound of Formula (I), (Ia) or (Ib) as defined above in the firstaspect of the invention for use in the treatment or prevention of aneurological disease or disorder. In a related aspect, the inventionprovides a pharmaceutical composition for use in treating or preventinga neurological disease or disorder wherein said composition comprises atherapeutically effective amount of a compound of Formula (I), (Ia) or(Ib) sufficient for treating or preventing a neurological disease ordisorder. In another related aspect, the invention provides a compoundof Formula (I), (Ia) or (Ib) or a pharmaceutical composition for thetreatment or prevention of a neurological disease or disorder whereinsaid neurological disease or disorder chosen from Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, orFrontotemporal Dementia, or Dementia with Lewy Bodies, and furtherwherein said composition preferably comprises a therapeuticallyeffective amount of the compound of Formula (I), (Ia) or (Ib) sufficientfor treating or preventing the said neurological disease or disorder. Ina preferred aspect, the therapeutically effective amount of a compoundof Formula (I), (Ia) or (Ib) is an amount sufficient to inhibit LSD1. Inanother preferred aspect, the therapeutically effective amount of acompound of Formula (I), (Ia) or (Ib) is an amount sufficient tomodulate the level of histone-3 lysine-4 methylation

In a still yet aspect, the invention provides a method for identifying acompound which is a selective inhibitor of LSD1, the method comprisingselecting or providing a compound of Formula (I) and determining theability of the said compound to inhibit LSD1 and MAO-A and/or MAO-B,wherein a compound that inhibits LSD1 to a greater extent than MAO-Aand/or MAO-B is identified as a LSD1 selective inhibitor. Thus, theinvention provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), (Ia)or (Ib) which is a selective inhibitor of LSD1. LSD1 selectiveinhibitors have Ki (IC50) values for LSD1 which are lower than the Ki(IC50) value for MAO-A and/or MAO-B. Preferably, the Ki (IC50) valuesfor LSD1 are two-fold lower than for MAO-A and/or MAO-B. In one aspectof this embodiment, the LSD1 Ki value is at least 5-fold lower than theKi (IC50) value for MAO-A and/or MAO-B. In one aspect of thisembodiment, the LSD1 Ki (IC50) value is at least 10-fold lower than theKi (IC50) value for MAO-A and/or MAO-B. In one embodiment of this aspectof the invention, the pharmaceutical composition comprising a LSD1selective inhibitor of Formula (I), (Ia) or (Ib) or a pharmaceuticallyacceptable salt or solvate thereof is useful for treating and/orpreventing a disease in an individual. In one specific embodiment, atherapeutically effective amount of the composition is administered toan individual in an amount sufficient to prevent or treat a disease ordisorder. In a more specific, the disease is cancer, a neurologicaldisease or condition, or a viral infection. In an even more specificaspect, the disease is a cancer chosen from prostate, testicular, brain,colorectal, lung, breast, skin, and blood cancer. In another aspect, theneurological disease or disorder is Huntington disease, Parkinsondisease, Alzheimer disease, Amyotrophic Lateral Sclerosis,Frontotemporal. Dementia, or Dementia with Lewy Bodies.

In a still yet aspect, the invention provides a method for identifying acompound which is a dual inhibitor of LSD1 and MAO-B, the methodcomprising selecting or providing a compound of Formula (I) anddetermining the ability of the said compound to inhibit LSD1 and MAO-Aand/or MAO-B, wherein a compound that inhibits LSD1 and MAO_B to agreater extent than MAO-A is identified as a LSD1/MAO-B dual inhibitor.Thus, the invention provides a pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of Formula (I), (Ia)or (Ib) which is a dual inhibitor of LSD1/MAO-B. LSD1/MAO-B dualinhibitors have Ki (IC50) values for LSD1 and MAO-B which are lower thanthe Ki (IC50) value for MAO-A. Preferably, the Ki (IC50) values for LSD1and MAO-B are two-fold lower than for MAO-A. In one aspect of thisembodiment, the LSD1/MAO-B dual inhibitors have Ki (IC50) values atleast 5-fold lower than the Ki (IC50) value for MAO-A. In one aspect ofthis embodiment, the LSD1/MAO-B Ki (IC50) values are at least 10-foldlower than the Ki (IC50) value for MAO-A. In one embodiment of thisaspect of the invention, the pharmaceutical composition comprising aLSD1/MAO-B dual inhibitor of Formula (I), (Ia) or (Ib) or apharmaceutically acceptable salt or solvate thereof is useful fortreating and/or preventing a disease in an individual. In one specificembodiment, a therapeutically effective amount of the composition isadministered to an individual in an amount sufficient to prevent ortreat a disease or disorder. In a more specific, the disease is cancer,a neurological disease or condition, or a viral infection. In an evenmore specific aspect, the disease is a cancer chosen from prostate,testicular, brain, colorectal, lung, breast, skin, and blood cancer. Inanother aspect, the neurological disease or disorder is Huntingtondisease, Parkinson disease, Alzheimer disease, Amyotrophic LateralSclerosis, Frontotemporal Dementia, or Dementia with Lewy Bodies.

Recent studies have implicated LSD1 in viral infection and reactivation.In particular it was shown that pharmacological inhibitors of LSD1 likeparnate and siRNA knock down of LSD1 caused reduced viral infectivityand reduced reactivation after latency (Liang et al. (2009) Nat. Med.15:1312-1317). Therefore it is believed that the compounds of theinvention can be used for treating or preventing viral infection.Furthermore, it is believed that the compounds of the invention cantreat or prevent viral reactivation after latency.

Thus, in another aspect, the invention provides a method for treating orpreventing a viral infection, the method comprising administering to anindividual (preferably a human) a compound of Formula (I), (Ia) or (Ib)as defined above in any of the aspects and embodiments of the inventionor a pharmaceutically acceptable salt or solvate thereof. Accordingly,the invention also provides a compound of Formula (I), (Ia) or (Ib) asdefined above in any of the aspects and embodiments of the invention ora pharmaceutically acceptable salt or solvate thereof for use intreating or preventing a viral infection. In one specific embodiment,the viral infection is a herpesvirus infection. In a more specificembodiment, the herpesvirus infection is caused by and/or associatedwith a herpesvirus chosen from HSV-1, HSV-2, and Epstein-Ban virus. Inanother embodiment of this seventh aspect, the viral infection is causedby and/or associated with HIV. In an even more specific embodiment, theinvention provides a method for treating or preventing viralreactivation after latency, the method comprising administering to anindividual (preferably a human) a compound of Formula (I), (Ia) or (Ib)as defined above in any of the aspects and embodiments of the inventionor a pharmaceutically acceptable salt or solvate thereof. Accordingly,the invention also provides a compound of Formula (I), (Ia) or (Ib) asdefined above in any of the aspects and embodiments of the invention ora pharmaceutically acceptable salt or solvate thereof for use intreating or preventing viral reactivation after latency. In a specificembodiment, the virus that is reactivating is a herpesvirus. In a morespecific embodiment, the herpesvirus that is reactivating is chosen fromHSV-1, HSV-2, and Epstein-Barr virus. In an even more specificembodiment, the virus that is reactivating is HSV.

During the inventors' investigation of amine oxidases like LSD1, MAO-Band MAO-A, it was unexpectedly found that the stereochemicalconfiguration of the cyclopropyl carbons of N-substitutedarylcyclopropylamine compounds substantially affects the potency of LSD1inhibition. The inventors have shown that the (−) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineis about 20-fold more active against LSD1 than the corresponding (+)stereoisomer. Furthermore, the (−) stereoisomer retained substantialMAO-B inhibitory activity. Notably, the selectivity for LSD1/MAO-A forthe (−)/(+) stereoisomer was over 100 fold as judged by k_(inact)/K_(I)values. Thus, (−) stereoisomers of the compounds of the presentinvention, including particularly the compounds of Formula (I), (Ia) and(Ib), are unexpectedly potent LSD1 inhibitors compared to theirrespective enantiomers. The invention thus relates to a compound ofFormula (I), (Ia) or (Ib) as described and defined herein, wherein thesubstituents on the cyclopropyl moiety (i.e., the group (A) and thegroup —NH—CH₂-(D)) are in trans-configuration and further wherein thecompound is optically active.

The invention, in one aspect, relates to a substantially pure, opticallyactive stereoisomer of a compound of Formula (I), (Ia) or (Ib) asdescribed and defined herein, wherein the substituents on thecyclopropyl moiety (i.e., the group (A) and the group —NH—CH₂-(D)) arein trans-configuration, or a pharmaceutically acceptable salt or solvatethereof, as well as its use in as a medicament. In a specific aspect,the substantially pure, optically active stereoisomer of a compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, is 90 mole-% or greater (−) stereoisomer and 10mole-% or less (+) stereoisomer. In a more specific aspect, thesubstantially pure, optically active stereoisomer is 95 mole-% orgreater (−) stereoisomer and 5 mole-% or less (+) stereoisomer. In yet amore specific aspect, the substantially pure, optically activestereoisomer is 98 mole-% or greater (−) stereoisomer and 2 mole-% orless (+) stereoisomer. In an even more specific aspect, thesubstantially pure, optically active stereoisomer is 99 mole-% orgreater (−) stereoisomer and 1 mole-% or less (+) stereoisomer. In yetan even more specific aspect, the substantially pure stereoisomer is99.5 mole-% or greater (−) stereoisomer and 0.5 mole-% or less (+)stereoisomer. The substantially pure, optically active stereoisomer of acompound of Formula (I), (Ia) or (Ib), wherein the substituents on thecyclopropyl moiety (i.e., the group (A) and the group —NH—CH₂-(D)) arein trans-configuration, is useful in treating or preventing a disease ordisorder, particularly cancer, depression, a neurodegenerative diseaseor disorder, or a viral infection.

The invention also relates to a composition comprising a stereoisomer ofa compound of Formula (I), (Ia) or (Ib), wherein the substituents on thecyclopropyl moiety (i.e., the group (A) and the group —NH—CH₂-(D)) arein trans-configuration, or a pharmaceutically acceptable salt or solvatethereof, wherein said composition has a 90% or more enantiomeric excessof the (−) stereoisomer of the compound. In a specific aspect saidcomposition has a 95% or more enantiomeric excess of the (−)stereoisomer of the compound. In a more specific aspect said compositionhas a 98% or more enantiomeric excess of the (−) stereoisomer of thecompound. In an even more specific aspect said composition has a 99% ormore enantiomeric excess of the (−) stereoisomer of the compound. Thecomposition, in one aspect, is for use in treating or preventing adisease or disorder, particularly cancer, depression, or aneurodegenerative disease or disorder, or a viral infection.

Accordingly, the invention relates to a compound of Formula (I), (Ia) or(Ib), wherein the substituents on the cyclopropyl moiety (i.e., thegroup (A) and the group —NH—CH₂-(D)) are in trans-configuration, or apharmaceutically acceptable salt or solvate thereof, wherein the (−)stereoisomer of said compound is present at an enantiomeric excess of90% or more, preferably of 95% or more, more preferably of 98% or more,and even more preferably of 99% or more.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a stereoisomer of a compound of Formula (I), (Ia)or (Ib), wherein the substituents on the cyclopropyl moiety (i.e., thegroup (A) and the group —NH—CH₂-(D)) are in trans-configuration, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier, wherein said composition has a 90%or more enantiomeric excess of the (−) stereoisomer of the compound. Ina specific aspect said composition has a 95% or more enantiomeric excessof the (−) stereoisomer of the compound. In a specific aspect saidcomposition has a 99% or more enantiomeric excess of the (−)stereoisomer of the compound. The pharmaceutical composition of thisaspect is particularly useful in treating or preventing cancer,depression, a neurodegenerative disease or disorder, or a viralinfection.

In one aspect, the invention relates to an optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, or a composition comprising any of the aforementionedcompounds, wherein said compound is the (1R, 2S) enantiomer (in respectto the substituents on the cyclopropyl ring) substantially free of the(1S, 2R) enantiomer. Preferably, the compound is more than 90 mole-%(1R, 2S) enantiomer and less than 10 mole-% (1S, 2R) enantiomer. Morepreferably, the compound is more than 95 mole-% (1R, 2S) enantiomer andless than 5 mole-% (1S, 2R) enantiomer. Yet more preferably, thecompound is more than 98 mole-% (1R, 2S) enantiomer and less than 2mole-% (1S, 2R) enantiomer. Even yet more preferably, the compound ismore than 99 mole-% (1R, 2S) enantiomer and less than 1 mole-% (1S, 2R)enantiomer. Still even more preferably, the compound is more than 99.5mole-% (1R, 2S) enantiomer and less than 0.5 mole-% (1S, 2R) enantiomer.The enantiomeric content can be determined, for example, by chiral HPLC(e.g., as described in Example 36).

In one aspect, the invention relates to an optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, or a composition comprising any of the aforementionedcompounds, wherein said compound is the (1S, 2R) enantiomer (in respectto the substituents on the cyclopropyl ring) substantially free of the(1R, 2S) enantiomer. Preferably, the compound is more than 90 mole-%(1S, 2R) enantiomer and less than 10 mole-% (1R, 2S) enantiomer. Morepreferably, the compound is more than 95 mole-% (1S, 2R) enantiomer andless than 5 mole-% (1R, 2S) enantiomer. Yet more preferably, thecompound is more than 98 mole-% (1S, 2R) enantiomer and less than 2mole-% (1R, 2S) enantiomer. Even yet more preferably, the compound ismore than 99 mole-% (1S, 2R) enantiomer and less than 1 mole-% (1R, 2S)enantiomer. Still even more preferably, the compound is more than 99.5mole-% (1S, 2R) enantiomer and less than 0.5 mole-% (1R, 2S) enantiomer.The enantiomeric content can be determined, for example, by chiral HPLC(e.g., as described in Example 36).

In one aspect, the invention relates to an optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, wherein the cyclopropyl ring carbon atom which is bound to theamino group of the compound has the (S)-configuration and thecyclopropyl ring carbon atom which is bound to the cyclic group (A)attached to the cyclopropyl ring of the compound has the(R)-configuration. Preferably, the compound is provided in anenantiomeric excess of at least 90%. Even more preferably the compoundis provided in an enantiomeric excess of at least 95%. Yet still morepreferably the compound is provided in an enantiomeric excess of atleast 98%. Still more preferably the compound is provided in anenantiomeric excess of at least 99%. The enantiomeric excess can bedetermined, for example, by chiral HPLC (e.g., as described in Example36).

In one aspect, the invention relates to an optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, wherein the cyclopropyl ring carbon atom which is bound to theamino group of the compound has the (R)-configuration and thecyclopropyl ring carbon atom which is bound to the cyclic group (A)attached to the cyclopropyl ring of the compound has the(S)-configuration. Preferably, the compound is provided in anenantiomeric excess of at least 90%. Even more preferably the compoundis provided in an enantiomeric excess of at least 95%. Yet still morepreferably the compound is provided in an enantiomeric excess of atleast 98%. Still more preferably the compound is provided in anenantiomeric excess of at least 99%. The enantiomeric excess can bedetermined, for example, by chiral HPLC (e.g., as described in Example36).

In one aspect, the invention relates to an optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, for use in treating or preventing a disease or disorder, suchas, e.g., cancer, a neurological disease, disorder or condition, or aviral infection. In one aspect, the neurological disease, disorder orcondition is depression, Huntington disease, Parkinson disease,Alzheimer disease, Amyotrophic Lateral Sclerosis, FrontotemporalDementia, or Dementia with Lewy Bodies. In one specific aspect, thecancer is prostate cancer. In another specific, the cancer is breastcancer. In another aspect, the cancer is lung cancer. In another aspect,the cancer is colorectal cancer. In another specific aspect, the canceris brain cancer. In another specific aspect, the cancer is skin cancer.In another specific aspect, the cancer is blood cancer (e.g., a leukemiaor a lymphoma; the leukemia to be treated or prevented includes, forexample, acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),or hairy cell leukemia). In one aspect, the neurological disease,disorder or condition is depression, Huntington disease, Parkinsondisease, or Alzheimer disease. In one aspect, the viral infection is aninfection with HSV1 or HSV2. In one aspect, the disease or disorder isdepression. In one aspect, the neurological disease, disorder orcondition is a neurodegenerative disease, disorder or condition. In oneaspect, the neurodegenerative disease. disorder or condition isHuntington disease, Parkinson disease, Alzheimer disease, AmyotrophicLateral Sclerosis, or Frontotemporal Dementia.

The invention further relates to the optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, as defined in any of the above embodiments or aspects, for usein the treatment or prevention of a disease or disorder, in particularcancer (e.g., breast cancer, lung cancer, prostate cancer, colorectalcancer, brain cancer, skin cancer, blood cancer, leukemia (including,for example, acute myelogenous leukemia (AML), chronic myelogenousleukemia (CML), chronic neutrophilic leukemia, chronic eosinophilicleukemia, chronic lymphocytic leukemia (CLL), acute lymphoblasticleukemia (ALL), or hairy cell leukemia), lymphoma, or myeloma), aneurological disease or condition (e.g., depression, Alzheimer'sdisease, Huntington disease, Parkinson's disease, or Dementia with LewyBodies), or a viral infection (e.g., a viral infection is caused byand/or associated with HIV, or a herpesvirus infection, such as aherpesvirus infection caused by and/or associated with a herpesviruschosen from HSV-1, HSV-2, or Epstein-Barr virus) in a subject(preferably a mammal, more preferably a human).

The invention further relates to the optically active compound ofFormula (I), (Ia) or (Ib), wherein the substituents on the cyclopropylmoiety (i.e., the group (A) and the group —NH—CH₂-(D)) are intrans-configuration, or a pharmaceutically acceptable salt or solvatethereof, as defined in any of the above embodiments or aspects, for usein the treatment or prevention of a disease or disorder wherein saiddisease or disorder is a neurodegenerative disease or disorder. In oneaspect, the neurodegenerative disease or disorder is Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis, orFrontotemporal Dementia.

In another preferred aspect, the invention is an optically activeN-substituted aryl- or heteroaryl cyclopropylamine, or pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treating orpreventing a disease or disorder. Preferably, the optically activeN-substituted aryl- or heteroaryl cyclopropylamine, as described herein,is a compound of Formula (II) or a pharmaceutically acceptable salt orsolvate thereof:R1^(II)-(A^(II))-R2^(II)  (II)wherein:(A^(II)) is an aryl or heteroaryl group having 2 substituents, R1^(II)and R2^(II), and 1, 2, or 3 optional substituents independently chosenfrom halo, C1-C3 alkyl, or C1-C3 alkoxy;R1^(II) is an -L₁ ^(II)-R3^(II) group;R3^(II) is an aryl or heterocyclyl group having 1, 2, 3, 4, or 5optional substituents independently chosen from halo, —OH, —NHSO₂R^(A),alkyl, alkoxy, cyano, —CF₃, or —OCF₃ wherein R^(A) is a C1-C6 alkyl orphenyl;L₁ ^(II) is chosen from a bond, —CH₂O—, —CH₂CH₂O—, —OCH₂—, —OCH₂CH₂—,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or —O—;R2^(II) is -Cyclopropyl-NH-L₂-R4 wherein said cyclopropyl group has twochiral centers substituted in the trans orientation corresponding to thecarbons to which (A^(II)) and —NH-L₂ ^(II)-R4^(II) are covalentlyattached;R4^(II) is a 5 or 6 membered heteroaryl ring having 1, 2, or 3 optionalsubstituents independently chosen from alkyl, —NH—R^(B), —OR^(B), orhalo wherein R^(B) is hydrogen, C1-C3 alkyl, or —C(═O)CH₃;L₂ ^(II) is a branched or unbranched C1-C4 alkylene groupand wherein said compound of Formula (II) is optically active.

Optically active compounds for use in the methods of the invention andoptically active compounds of the invention refer to enrichedstereoisomers of compounds wherein the enrichment is in reference to thechiral centers corresponding to the enantiomers of the trans-substitutedcyclopropyl moiety. Other chiral centers may or may not be present inthe molecule and the configuration or optical rotation attributable tothese centers are not intended to be addressed by this invention e.g.,their effect on LSD1, MAO-A, or MAO-B.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

Preferably, the optically active N-substituted aryl- or heteroarylcyclopropylamine, or pharmaceutically acceptable salt or solvatethereof, for use in a method of treating or preventing a disease ordisorder, as described herein, is of Formula (II):R1^(II)-(A^(II))-R2^(II)  (II)wherein:(A^(II)) is an aryl or heteroaryl group having 2 substituents, R1^(II)and R2^(II), and 1, 2, or 3 optional substituents independently chosenfrom halo, C1-C3 alkyl, or C1-C3 alkoxy;R1^(II) is an -L₁ ^(II)-R3^(II) group;R3^(II) is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2,or 3 optional substituents independently chosen from halo, —OH,—NHSO₂R^(A), alkyl, alkoxy, cyano, —CF₃, or —OCF₃ wherein R^(A) is C1-C6alkyl or phenyl;L₁ ^(II) is chosen from a bond, —CH₂O—, or —CH₂O—;R2^(II) is -Cyclopropyl-NH-L₂ ^(II)-R4^(II) wherein said cyclopropylgroup has two chiral centers substituted in the trans orientationcorresponding to the carbons to which (A^(u)) and —NH-L₂ ^(II)-R4^(II)are covalently attached;R4^(II) is a 5-membered heteroaryl ring having 1, 2, or 3 optionalsubstituents independently chosen from —NH₂ or —NH(C1-C3) alkyl;L₂ ^(II) is —CH₂— or —CH₂CH₂—;and wherein said compound of Formula (II) is optically active.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (II) as defined above, or a pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

Furthermore, the inventors have unexpectedly found that a subset ofoptically active compounds of Formula (II) as shown in Formula (III) arepotent and selective inhibitors of LSD1 or LSD1 and MAO-B.

The invention therefore is an optically active compound of Formula (III)or a pharmaceutically acceptable salt or solvate thereof:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is an aryl or heteroaryl group having 2 substituents, R1^(III)and R2^(III), and 1, 2, or 3 optional substituents wherein said optionalsubstituents are independently chosen from halo, C1-C3 alkyl, or C1-C3alkoxy;R1^(III) is an -L₁ ^(III)-R3^(III) group;R3^(III) is a phenyl, pyridyl, thiazolyl, or thienyl group having 1, 2,3, 4, or 5 optional substituents independently chosen from halo, —OH,—NHSO₂R^(A), alkyl, alkoxy, cyano, —CF₃, or —OCF₃ wherein R^(A) is aC1-C6 alkyl or phenyl;L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said cyclopropylgroup has two chiral centers substituted in the trans orientationcorresponding to the carbons to which (A^(III)) and —NH-L₂^(III)-R4^(III) are covalently attached;R4^(III) is a 5-membered heteroaryl ring having 1, 2, or 3 optionalsubstituents independently chosen from —NH₂ or —NH(C1-C3) alkyl;L₂ ^(III) is —CH₂— or —CH₂CH₂—;and wherein said compound of Formula (III) is optically active.

Preferably, the optically active compound of Formula (III) is asfollows:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is a phenyl or pyridyl group having 2 substituents, R1^(III)and R2^(III);R1^(III) is an -L₁ ^(III)-R3^(III) group;R3^(III) is a phenyl having 0, 1, 2, or 3 substituents independentlychosen from —F, —Cl, —OH, —NHSO₂R^(A), C1-C3 alkyl, C1-C3 alkoxy, cyano,—CF₃, or —OCF₃ wherein R^(A) is C1-C6 alkyl or phenyl;L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said cyclopropylgroup has two chiral centers corresponding to the carbons to which(A^(III)) and —NH-L₂ ^(III)-R4^(III) are covalently attached;R4 is a 5-membered heteroaryl ring wherein said the chain of atomscomprising said 5-membered heteroaryl ring has 2 or 3 hetero atomsindependently chosen from N, S, or O, wherein said 5 membered heteroarylhas 1 optional substituent wherein said optional substituent is —NH₂ or—NH(C1-C3) alkyl;L₂ ^(III) is —CH₂— or —CH₂CH₂—;or a pharmaceutically acceptable salt or solvate thereof,and wherein said compound of Formula (III) is optically active.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

Even more preferably, the optically active compound of Formula (III) isas follows:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is a phenyl or pyridyl group having 2 substituents, R1^(III)and R2^(III);R1^(III) is an -L₁ ^(III)-R3^(III) group;R3^(III) is a phenyl having 1, 2, or 3 optional substituentsindependently chosen from —F, —Cl, —OH, —NHSO₂CH₃, methyl, methoxy,cyano, —CF₃, or —OCF₃;L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said cyclopropylgroup has two chiral centers substituted in the trans orientationcorresponding to the carbons to which (A^(III)) and —NH-L₂^(III)-R4^(III) are covalently attached;R4^(III) is an oxadiazolyl, thiadiazolyl, or thiazolyl ring having 1optional substituent wherein said optional substituent is —NH₂ or—NH(C1-C3) alkyl;L₂ ^(III) is —CH₂— or —CH₂CH₂—;or a pharmaceutically acceptable salt or solvate thereof,and wherein said compound of Formula (III) is optically active.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

Preferably, the optically active compound of Formula (III) is asfollows:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is a phenyl or pyridyl group having 2 substituents, R1^(III)and R2^(III);R1^(III) is an -L₁ ^(III)-R3^(III) group;R3^(III) is a phenyl having 0, 1, 2, or 3 substituents independentlychosen from —F, Cl—, —OH, —NHSO₂R^(A), C1-C3 alkyl, C1-C3 alkoxy, cyano,—CF₃, or —OCF₃ wherein R^(A) is C1-C6 alkyl or phenyl;

-   -   L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;        R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said        cyclopropyl group has two chiral centers substituted in the        trans orientation corresponding to the carbons to which        (A^(III)) and —NH-L₂ ^(III)-R4^(III) are covalently attached;        R4^(III) is a 5-membered heteroaryl ring wherein said the chain        of atoms comprising said 5-membered heteroaryl ring has 2 or 3        hetero atoms independently chosen from N, S, or O, having 1        optional substituent wherein said optional substituent is —NH₂        or —NH(C1-C3) alkyl;        L₂ ^(III) is —CH₂— or —CH₂CH₂—;        or a pharmaceutically acceptable salt or solvate thereof,        and wherein said compound of Formula (III) is optically active.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

Even more preferably, the optically active compound of Formula (III) isas follows:R1^(III)-(A^(III))-R2^(III)  (III)wherein:(A^(III)) is a phenyl or pyridyl group having 2 substituents, R1^(III)and R2^(III);R1^(III) is an -L₁ ^(III)-R3^(III) group;R3^(III) is a phenyl having 0, 1, 2, or 3 substituents independentlychosen from —F, —Cl, —OH, —NHSO₂CH₃, methyl, methoxy, cyano, —CF₃, or—OCF₃;L₁ ^(III) is chosen from a bond, —OCH₂—, or —CH₂O—;R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said cyclopropylgroup has two chiral centers substituted in the trans orientationcorresponding to the carbons to which (A^(III)) and —NH-L₂^(III)-R4^(III) are covalently attached;R4^(III) is a heteroaryl group which is amide isostere having 1 optionalsubstituent wherein said optional substituent is —NH₂ or —NH(C1-C3)alkyl;L₂ ^(III) is —CH₂— or —CH₂CH₂—;or a pharmaceutically acceptable salt or solvate thereof,and wherein said compound of Formula (III) is optically active.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier.

The invention is also is a pharmaceutical composition comprising anoptically active N-substituted aryl- or heteroaryl cyclopropylamine ofFormula (III) as defined above, or pharmaceutically acceptable salt orsolvate thereof, and a pharmaceutically acceptable carrier, for use intreating or preventing a disease or disorder.

In one aspect, the invention is an optically active N-substituted aryl-or heteroaryl-cyclopropylamine for use in a method of treating orpreventing a disease or disorder. In a specific aspect, the disease ordisorder is a human disease or disorder chosen from cancer, depression,a neurodegenerative disease or condition, or a viral infection. In oneaspect, the neurodegenerative disease or disorder is Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis,Frontotemporal Dementia, or Dementia with Lewy Bodies. In a specificaspect, the optically active N-substituted aryl- orheteroaryl-cyclopropylamine is as defined in Formula (II) or (III).

The invention, in one aspect, is a substantially pure stereoisomer of anN-substituted aryl- or heteroaryl-cyclopropylamine (e.g., a compound ofFormula (II) or (III) as described herein) or a pharmaceuticallyacceptable salt or solvate thereof, for use in a method of treating orpreventing a disease or disorder. In a related aspect, the methodcomprises administering to an individual a therapeutically effectiveamount of a substantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine. Desirably, the disease or disorder is onethat is treatable or preventable by LSD1 inhibition, LSD1 inhibition andMAO-B inhibition, or MAO-B inhibition. In a specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 90% or greater (−) stereoisomer and10% or less (+) stereoisomer. In a more specific aspect, a substantiallypure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 95% or greater (−) stereoisomer and5% or less (+) stereoisomer. In yet a more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 98% or greater (−) stereoisomer and2% or less (+) stereoisomer. In an even more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 99% or greater (−) stereoisomer and1% or less (+) stereoisomer. In yet an even more specific aspect, asubstantially pure stereoisomer of an N-substituted aryl- orheteroaryl-cyclopropylamine refers to an N-substituted aryl- orheteroaryl-cyclopropylamine which is 99.5% or greater (−) stereoisomerand 0.5% or less (+)stereoisomer. In one embodiment, the above-describedpercentages refer to mole-%. The substantially pure stereoisomer of anN-substituted aryl- or heteroaryl-cyclopropylamine of this aspect isuseful in treating or preventing cancer, depression, a neurodegenerativedisease or disorder, or a viral infection. In a specific aspect, theoptically active N-substituted aryl- or heteroaryl-cyclopropylamine isas defined in Formula (II) or (III).

Furthermore, in another aspect, the invention is a compositioncomprising a stereoisomer of an N-substituted aryl- or heteroarylcyclopropylamine (e.g., a compound of Formula (II) or (III) as describedherein), or a pharmaceutically acceptable salt or solvate thereof,wherein said composition has a 90% or more enantiomeric excess of the(−) stereoisomer of the N-substituted aryl- orheteroaryl-cyclopropylamine. In a specific aspect said composition has a95% or more enantiomeric excess of the (−) stereoisomer of theN-substituted aryl- or heteroaryl-cyclopropylamine. In a more specificaspect said composition has a 98% or more enantiomeric excess of the (−)stereoisomer of the N-substituted aryl- or heteroaryl-cyclopropylamine.In an even more specific aspect said composition has a 99% or moreenantiomeric excess of the (−) stereoisomer of the N-substituted aryl-or heteroaryl-cyclopropylamine. The composition, in one aspect, is foruse in treating or preventing cancer, depression, or a neurodegenerativedisease or disorder, or a viral infection. In a specific aspect, theoptically active N-substituted aryl- or heteroaryl-cyclopropylamine isas defined in Formula (II) or (III).

Furthermore, in another aspect, the invention is a pharmaceuticalcomposition comprising a stereoisomer of an N-substituted aryl- orheteroaryl cyclopropylamine (e.g., a compound of Formula (II) or (III)as described herein), or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier wherein saidcomposition has a 90% or more enantiomeric excess of the (−)stereoisomer of the N-substituted aryl- or heteroaryl-cyclopropylamine.In a specific aspect said composition has a 95% or more enantiomericexcess of the (−) stereoisomer of the N-substituted aryl- orheteroaryl-cyclopropylamine. In a specific aspect said composition has a99% or more enantiomeric excess of the (−) stereoisomer of theN-substituted aryl- or heteroaryl-cyclopropylamine. The pharmaceuticalcomposition of this aspect is useful in treating or preventing cancer,depression, a neurodegenerative disease or disorder, or a viralinfection. In a specific aspect, the optically active N-substitutedaryl- or heteroaryl-cyclopropylamine is as defined in Formula (II) or(III).

In one aspect, the invention is a composition as defined hereincomprising an optically active N-substituted aryl- orheteroaryl-cyclopropylamine of Formula (II) or (III), as described inany one of the above embodiments or aspects, or a solvate or apharmaceutically acceptable salt thereof, wherein said N-substitutedaryl- or heteroaryl-cyclopropylamine is the (1R, 2S) enantiomer (inrespect to the substituents on the cyclopropyl ring) substantially freeof the (1S, 2R) enantiomer. Preferably, the N-substituted aryl- orheteroaryl-cyclopropylamine is more than 90% (1R, 2S) enantiomer andless than 10% (1S, 2R) enantiomer. More preferably, the N-substitutedaryl- or heteroaryl-cyclopropylamine is more than 95% (1R, 2S)enantiomer and less than 5% (1S, 2R) enantiomer. Yet more preferably,the N-substituted aryl- or heteroaryl-cyclopropylamine is more than 98%(1R, 2S) enantiomer and less than 2% (1S, 2R) enantiomer. Even yet morepreferably, the N-substituted aryl- or heteroaryl-cyclopropylamine ismore than 99% (1R, 2S) enantiomer and less than 1% (1S, 2R) enantiomer.Still even more preferably, the N-substituted aryl- orheteroaryl-cyclopropylamine is more than 99.5% (1R, 2S) enantiomer andless than 0.5% (1S, 2R) enantiomer. The enantiomeric content can bedetermined, for example, by chiral HPLC e.g., (as described in Example36).

In one aspect, the invention is a composition as defined hereincomprising an optically active N-substituted aryl- orheteroaryl-cyclopropylamine of Formula (II) or (III), as described inany one of the above embodiments or aspects, or a solvate or apharmaceutically acceptable salt thereof, wherein said N-substitutedaryl- or heteroaryl-cyclopropylamine is the (1S, 2R) enantiomer (inrespect to the substituents on the cyclopropyl ring) substantially freeof the (1R, 2S) enantiomer. Preferably, the N-substituted aryl- orheteroaryl-cyclopropylamine is more than 90% (1S, 2R) enantiomer andless than 10% (1R, 2S) enantiomer. More preferably, the N-substitutedaryl- or heteroaryl-cyclopropylamine is more than 95% (1S, 2R)enantiomer and less than 5% (1R, 2S) enantiomer. Yet more preferably,the N-substituted aryl- or heteroaryl-cyclopropylamine is more than 98%(1S, 2R) enantiomer and less than 2% (1R, 2S) enantiomer. Even yet morepreferably, the N-substituted aryl- or heteroaryl-cyclopropylamine ismore than 99% (1S, 2R) enantiomer and less than 1% (1R, 2S) enantiomer.Still even more preferably, the N-substituted aryl- orheteroaryl-cyclopropylamine is more than 99.5% (1S, 2R) enantiomer andless than 0.5% (1R, 2S) enantiomer. The enantiomeric content can bedetermined, for example, by chiral HPLC e.g., (as described in Example36).

In one aspect, the invention is an optically active N-substituted aryl-or heteroaryl cyclopropylamine (e.g., a compound of Formula (II) or(III)), as defined in any one of the above embodiments or aspects, or asolvate or a pharmaceutically acceptable salt or solvate thereof,wherein the cyclopropyl ring carbon atom which is bound to the aminogroup of the N-substituted aryl- or heteroaryl-cyclopropylamine has the(S)-absolute configuration and the cyclopropyl ring carbon atom which isbound to the cyclic group adjacent to the cyclopropyl ring of theN-substituted aryl- or heteroaryl-cyclopropylamine has the (R)-absoluteconfiguration. Preferably, said N-substituted aryl- orheteroaryl-cyclopropylamine is provided in an enantiomeric excess of atleast 90%. Even more preferably said N-substituted aryl- orheteroaryl-cyclopropylamine is provided in an enantiomeric excess of atleast 95%. Yet still more preferably said compound is provided in anenantiomeric excess of at least 98%. Still more preferably saidN-substituted aryl- or heteroaryl-cyclopropylamine is provided in anenantiomeric excess of at least 99%. The enantiomeric excess can bedetermined, for example, by chiral HPLC e.g., (as described in Example36).

In one aspect, the invention provides an optically active N-substitutedaryl- or heteroaryl cyclopropylamine (e.g., a compound of Formula (II)or (III)), as defined in any one of the above embodiments or aspects, ora pharmaceutically acceptable salt or solvate thereof, wherein thecyclopropyl ring carbon atom which is bound to the amino group of thecompound has the (R) absolute configuration and the cyclopropyl ringcarbon atom which is bound to the cyclic group adjacent to thecyclopropyl ring of the compound has the (S) absolute configuration.Preferably, said compound is provided in an enantiomeric excess of atleast 90%. Even more preferably said compound is provided in anenantiomeric excess of at least 95%. Yet still more preferably saidcompound is provided in an enantiomeric excess of at least 98%. Stillmore preferably said compound is provided in an enantiomeric excess ofat least 99%. The enantiomeric excess can be determined, for example, bychiral HPLC e.g., (as described in Example 36).

In one aspect, the invention is an optically active N-substituted aryl-or heteroaryl-cyclopropylamine (e.g., a compound of Formula (II) or(III) as described herein), or a pharmaceutically acceptable salt orsolvate thereof, for use in treating or preventing a disease ordisorder. In a related aspect, the method comprises administering to anindividual in need of treatment a therapeutically effective amount of anoptically active N-substituted aryl- or heteroaryl-cyclopropylamine or apharmaceutically acceptable salt or solvate thereof. In one aspect, thedisease or disorder is a human disease or disorder chosen from cancer, aneurological disease or condition, or a viral infection. In one aspect,the neurological disease or disorder is depression, Huntington disease,Parkinson disease, Alzheimer disease, Amyotrophic Lateral Sclerosis,Frontotemporal Dementia, or Dementia with Lewy Bodies. In one specificaspect, the cancer is prostate cancer. In another specific, the canceris breast cancer. In another aspect, the cancer is lung cancer. Inanother aspect, the cancer is colorectal cancer. In another specificaspect, the cancer is brain cancer. In another specific aspect, thecancer is skin cancer. In another specific aspect, the cancer is bloodcancer (e.g., a leukemia (including, for example, acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilicleukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia(CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia) or alymphoma). In another specific aspect, the cancer is a myeloma. In oneaspect, the neurological disease or condition is depression, Huntingtondisease, Parkinson disease, or Alzheimer disease. In one aspect, theviral infection is HSV1 or HSV2. In one aspect, the disease or conditionis depression. In one aspect, the neurological disease or condition is aneurodegenerative disease or condition. In one aspect, theneurodegenerative disease or disorder is Huntington disease, Parkinsondisease, Alzheimer disease, Amyotrophic Lateral Sclerosis, orFrontotemporal Dementia. In one aspect, the neurodegenerative disease ordisorder is Huntington disease. In one aspect, the neurodegenerativedisease or disorder is Parkinson disease. In one aspect, theneurodegenerative disease or disorder is Alzheimer disease. In oneaspect, the neurodegenerative disease or disorder is Amyotrophic LateralSclerosis. In one aspect, the neurodegenerative disease or disorder isFrontotemporal Dementia.

The invention further relates to the optically active N-substitutedaryl- or heteroaryl cyclopropylamine of Formula (II) or (III), or apharmaceutically acceptable salt or solvate thereof, as defined in theabove embodiments or aspects, for use in the treatment or prevention ofa disease or disorder, in particular cancer (e.g., breast cancer, lungcancer, prostate cancer, colorectal cancer, brain cancer, skin cancer,blood cancer, leukemia (including, for example, acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilicleukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia(CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia),lymphoma, or myeloma), a neurological disease or condition (e.g.,depression, Alzheimer's disease, Huntington disease, Parkinson'sdisease, or Dementia with Lewy Bodies), or a viral infection (e.g., aviral infection is caused by and/or associated with HIV, or aherpesvirus infection, such as a herpesvirus infection caused by and/orassociated with a herpesvirus chosen from HSV-1, HSV-2, or Epstein-Barrvirus) in a subject (preferably a mammal, more preferably a human).

The invention further relates to the optically active N-substitutedaryl- or heteroaryl cyclopropylamine of Formula (II) or (III), or apharmaceutically acceptable salt or solvate thereof, as defined inanyone of the above embodiment, for use in the treatment or preventionof a disease or disorder wherein said disease or disorder is aneurodegenerative disease or disorder. In one aspect, theneurodegenerative disease or disorder is Huntington disease, Parkinsondisease, Alzheimer disease, Amyotrophic Lateral Sclerosis, orFrontotemporal Dementia.

In one embodiment the invention provides a compound Formula (I), (Ia) or(Ib) or a solvate or a pharmaceutically acceptable salt thereof, whereinthe compound is:

-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine;-   3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   4′-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino    ethyl)-1,3,4-oxadiazol-2-yl)acetamide;-   4′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;-   5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;-   4-((((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;-   2-((((trans)-2-(4-(benzyl    oxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine;    or-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine.

In one embodiment of the invention provides a pharmaceutical compositioncomprising a pharmaceutically carrier and a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is:

-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine;-   3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   4′-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   4′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;-   5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;-   4-((((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine;    or-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine;

In one embodiment of the invention relates to a compound, or a solvateor a pharmaceutically acceptable salt thereof wherein said compound is:

-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine;-   3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   4′-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   4′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;-   5-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;-   4-((((trans)-2-(3′-(trifluoromethyl)[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine;    or-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine;    for use in a method of treating or preventing a neurological disease    or condition. In one aspect, the neurological disease or condition    is chosen from Alzheimer Disease, Parkinson Disease, Huntington    Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or    Dementia with Lewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is:

-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine;-   5-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine;-   3-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl-phenol;-   3-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol;-   4′-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   N-(5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   4′-((trans)-2-(5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;-   5-((((trans)-2-(6-(3-(tri fluoromethyl)phenyl)pyridin-3-yl)cycloprop    yl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   2-((((trans)-2-(4-(benzyl    oxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;-   4-((((trans)-2-(3′-trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine;-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine;-   2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine;-   6-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine;    or-   3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine;    for use in a method of treating or preventing cancer. In one aspect,    the cancer is chosen from prostate, testicular, brain, colorectal,    lung, breast, lymphoma, skin, or blood cancer.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is:

-   4′-((trans)-2-((2-aminothiazol-5-yl)methyl    amino)cyclopropyl)biphenyl-3-ol;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;-   5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;    or-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;    for use in a method of treating or preventing a neurological disease    or condition. In one aspect, the neurological disease or condition    is chosen from Alzheimer Disease, Parkinson. Disease, Huntington    Disease, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or    Dementia with Lewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol,

for use in a method of treating or preventing a neurological disease orcondition. In one aspect, the neurological disease or condition ischosen from Alzheimer Disease, Parkinson Disease, Huntington Disease,Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia withLewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine,for use in a method of treating or preventing a neurological disease orcondition. In one aspect, the neurological disease or condition ischosen from Alzheimer Disease, Parkinson Disease, Huntington Disease,Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia withLewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine,for use in a method of treating or preventing a neurological disease orcondition. In one aspect, the neurological disease or condition ischosen from Alzheimer Disease, Parkinson Disease, Huntington Disease,Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia withLewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof wherein said compound is5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine,for use in a method of treating or preventing a neurological disease orcondition. In one aspect, the neurological disease or condition ischosen from Alzheimer Disease, Parkinson Disease, Huntington Disease,Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia withLewy Bodies.

In one embodiment the invention relates to a compound, or a solvate or apharmaceutically acceptable salt thereof, wherein said compound is5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine,for use in a method of treating or preventing a neurological disease orcondition. In one aspect, the neurological disease or condition ischosen from Alzheimer Disease, Parkinson Disease, Huntington Disease,Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, or Dementia withLewy Bodies.

In one embodiment of the invention provides an optically activeN-substituted aryl- or heteroaryl cyclopropylamine or a pharmaceuticallyacceptable salt or solvate thereof, wherein said optically activeN-substituted aryl- or heteroaryl-cyclopropylamine is chosen from

-   (−)    5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   (−)    N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;

(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;

-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;    or-   (−)    5-((((trans)-2-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine.

In a related aspect, the invention relates to a compound selected from:

-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   (−)    5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   (−)    N-(5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   (−)    5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;    or    a pharmaceutically acceptable salt or solvate thereof;    for use in a method of treating or preventing a neurological disease    or condition (e.g., depression). Preferably, the neurological    disease or condition is chosen from depression, Alzheimer disease,    Huntington disease, Parkinson disease, Frontotemporal Dementia,    Dementia with Lewy Bodies, or Amyotrophic Lateral Sclerosis.

The invention thus is a compound or composition having an opticallyactive N-substituted aryl- or heteroaryl-cyclopropylamine. Preferably,the optically active N-substituted aryl- or heteroaryl-cyclopropylamineis as defined herein in any one of the embodiments or aspects of Formula(II) or (III). More preferably, the optically active N-substituted aryl-or heteroaryl-cyclopropylamine has a kinact/KI value for LSD1 which isat least 50 fold higher than the kinact/KI value for MAO-A. Still morepreferably, the kinact/Ki value for LSD1 is at least 100-fold higherthan kinact/KI for MAO-A. Even more preferably, the LSD1 kinact/KI valueis at least 250-fold higher than the kinact/KI value for MAO-A. Yet evenmore preferably, the LSD1 kinact/KI value is at least 500-fold higherthan the kinact/KI value for MAO-A.

Preferably, the optically active N-substituted aryl- orheteroaryl-cyclopropylamine is as defined herein in any one of theembodiments or aspects of Formula (II) or (III). More preferably, theoptically active N-substituted aryl- or heteroaryl-cyclopropylamine haskinact/KI value for LSD1 and MAO-B which are at least 50-fold higherthan the kinact/Ki value for MAO-A. Preferably, the kinact/KI value forLSD1 and MAO-B are at least 1.00-fold higher than kinact/KI for MAO-A.Even more preferably, the LSD1 and MAO-B kinact/KI values are at least250-fold higher than the kinact/KI value for MAO-A. Yet even morepreferably, the LSD1 and MAO-B kinact/KI values are at least 500-foldhigher than the kinact/KI value for MAO-A.

Preferably, the optically active N-substituted aryl- orheteroaryl-cyclopropylamine is as defined herein in any of theembodiments of Formula (I) or (II). More preferably, the opticallyactive N-substituted aryl- or heteroaryl-cyclopropylamine has akinact/KI value for MAO-B which is at least 50-fold higher than thekinact/KI value for MAO-A. Preferably, the kinact/KI value for MAO-B isat least 100-fold higher than kinact/KI for MAO-A. Even more preferably,the MAO-B kinact/KI value is at least 500-fold higher than the kinact/KIvalue for MAO-A. Yet even more preferably, the MAO-B kinact/KI is atleast 1000-fold higher than the kinact/KI value for MAO-A. Yet evenstill more preferably, the MAO-B kinact/KI value is at least 2000-foldhigher than the kinact/KI value for MAO-A.

The optically active N-substituted aryl- or heteroaryl-cyclopropylamine,pharmaceutical composition comprising the optically active N-substitutedaryl- or heteroaryl-cyclopropylamine, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, and methods oftheir use have unexpected selectivity for LSD1 and/or MAOB. The (−)stereoisomers of N-substituted aryl- or heteroaryl-cyclopropylamines(e.g., of the compounds of Formula (II) or (III) as described herein)are unexpectedly potent and selective inhibitors of LSD1 and/or MAO-B.Avoiding inhibition of “off-targets” can avoid unwanted or undesirableside-effects like the cheese effect associated with MAO-A.

The optically active compounds of the invention can be prepared bychiral HPLC from e.g., racemates, chiral synthesis with compounds ofknown chirality, or chiral recrystallization using chiral salts.

In one aspect, the invention provides a method for enriching anenantiomer of a trans N-substituted cyclopropylamine (e.g., anenantiomer of a compound of Formula (II) or (III) or an enantiomer of acompound of Formula (I), wherein the substituents on the cyclopropylmoiety comprised in Formula (I) (i.e., the substituent (A) and thesubstituent —NH—CH₂-(D)) are in trans-configuration, the methodcomprising: contacting a trans-substituted cyclopropylamine with achiral recrystallization agent in a solvent (particularly underconditions that are sufficient for the crystallization of the salt ofthe chiral recrystallization agent and the trans substitutedcylopropylamine); and isolating the crystallized salt of the chiralrecrystallization agent and the trans substituted cyclopropylamine. Inanother preferred aspect, the trans cyclopropylamine is trans4-benzoxy-2-phenylcyclopropylamine or a protected derivative thereof. Ina preferred aspect, the trans N-substituted cyclopropylamine is ofFormula (II) or (III) as described above or a derivative thereof whereinthe -L2^(II)-R4^(II) group or the -L2^(III)-R4^(III) group is absent orsubstituted with a protecting group. In a preferred aspect, the chiralrecrystallization agent is chosen from S (+) mandelic acid, D (−)tartaric acid, L (−) di-p-toluoyl tartaric acid, or R (−) mandelic acid.In one preferred aspect, the chiral recrystallization agent is R (−)mandelic acid. In one aspect, the solvent is THF and H₂O.

In one aspect, the invention provides a method for preparing anenantiomer of a trans N-substituted cyclopropylamine comprising:contacting a trans-substituted cyclopropylamine with a chiralrecrystallization agent in a solvent (particularly under conditions aresufficient for the crystallization for the salt of the chiralrecrystallization agent and the trans substituted cyclopropylamine); andisolating the crystallized salt of the chiral recrystallization agentand the trans substituted cyclopropylamine, thereby preparing anenantiomer of a trans N-substituted cyclopropylamine. In a preferredaspect, the trans N-substituted cyclopropylamine is of Formula (II) or(III) as defined above or a derivative thereof wherein the-L2^(II)-R4^(II) group or the -L2^(III)-R4^(III) group is absent orsubstituted with a protecting group. In another preferred aspect, thetrans cyclopropylamine is trans 4-benzoxy-2-phenylcyclopropylamine or aprotected derivative thereof. In a preferred aspect, the chiralrecrystallization agent is chosen from S (+) mandelic acid, D (−)tartaric acid, L (−) di-p-toluoyl tartaric acid, or R (−) mandelic acid.In one preferred aspect, the chiral recrystallization agent is R (−)mandelic acid. In one aspect, the solvent is THF and H₂O.

Additionally, the invention relates to the (+) enantiomer of a transN-substituted aryl- or heteroaryl-cyclopropylamine, including thecompounds of Formula (II) or (III) and the compounds of Formula (I), inwhich the substituents on the cyclopropylamine moiety are intrans-orientation. For example, a corresponding optically active (+)enantiomer may be selected from:

-   (+)    5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   (+) 5-((((trans)-2-(4-(benzyl    oxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   (+)    N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   (+)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;-   (+)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;-   (+)-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;    or a pharmaceutically acceptable salt or solvate thereof.

The present invention furthermore relates to the following items:

-   1. An optically active N-substituted aryl- or    heteroaryl-cyclopropylamine or a pharmaceutically acceptable salt or    solvate thereof for use in a method for treating or preventing a    disease.-   2. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 wherein said N-substituted    aryl- or heteroaryl cyclopropylamine is a trans N-substituted aryl-    or heteroaryl cyclopropylamine that rotates plane polarized light in    the (−) sense or is the (−) stereoisomer.-   3. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 wherein said    N-substituted aryl- or heteroaryl cyclopropylamine is 90% or greater    (−) stereoisomer and 10% or less (+) steroisomer.-   4. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 wherein said    N-substituted aryl- or heteroaryl cyclopropylamine is 95% or greater    (−) stereoisomer and 5% or less (+).-   5. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 wherein said    N-substituted aryl- or heteroaryl. cyclopropylamine is 98% or    greater (−) stereoisomer and 2% or less (+).-   6. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 wherein said    N-substituted aryl- or heteroaryl cyclopropylamine is 99% or greater    (−) stereoisomer and 1% or less (+).-   7. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine is 99.5% or    greater (−) stereoisomer and 0.5% or less (+).-   8. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 having a 90% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   9. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 1 or 2 having a 95% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   10. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 1 or 2 having a 98% or more enantiomeric    excess of the (−) stereoisomer of the N-substituted aryl- or    heteroaryl-cyclopropylamine.-   11. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 1 or 2 having a 99% or more enantiomeric    excess of the (−) stereoisomer of the N-substituted aryl- or    heteroaryl-cyclopropylamine.-   12. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any of items 1-11, or a pharmaceutically    acceptable salt thereof, wherein said N-substituted aryl- or    heteroaryl cyclopropylamine is of Formula (II):    R1^(II)-(A^(II))-R2^(II)    -   wherein (A^(II)) is an aryl or heteroaryl group having 2        substituents, R1^(II) and R2^(II), and 1 to 3 optional        substituents wherein said optional substituents are        independently chosen from halo, C1-C3 alkyl, or C1-C3 alkoxy;    -   R1^(II) is an -L₁-R3 group;    -   R3^(II) is a aryl or heteroaryl group having 1, 2, 3, 4, or 5        optional substituents independently chosen from halo, —OH,        —NHSO₂R^(A), alkyl, alkoxy, cyano, —CF₃, or —OCF₃ wherein R^(A)        is a C1-C6 alkyl or phenyl;    -   L₁ ^(II) is chosen from a bond, —CH₂O—, —CH₂CH₂O—, —OCH₂—,        —OCH₂CH₂—, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, or —O—.    -   R2^(II) is -Cyclopropyl-NH-L₂ ^(II)-R4^(II) wherein said        cyclopropyl group has two chiral centers substituted in the        trans orientation corresponding to the carbons to which (A^(II))        and —NH-L₂ ^(II)-R4^(II) are covalently attached;    -   R4^(II) is a 5 or 6 membered heteroaryl ring having 1, 2, or 3        optional substituents wherein said optional substituents are        independently chosen from alkyl, NHR^(B), —OR^(B), or halo        wherein R^(B) is a hydrogen, C1-C3 alkyl, or —C(═O)CH₃;    -   L₂ ^(II) is a branched or unbranched C1-C4 alkylene group.-   13. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of item 12 wherein (A^(II)) is an aryl    or heteroaryl group having 2 substituents, R1^(II) and R2^(II), and    1, 2, or 3 optional substituents wherein said optional substituents    are independently chosen from halo, C1-C3 alkyl, or C1-C3 alkoxy.-   14. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 12 wherein R3^(II) is a phenyl, pyridyl,    thiazolyl, or thienyl group having 1, 2, or 3 optional substituents    independently chosen from halo, —OH, —NHSO₂R^(A), alkyl, alkoxy,    cyano, —CF₃, or —OCF₃ wherein R^(A) is C1-C6 alkyl or phenyl.-   15. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 12 wherein L₁ ^(II) is chosen from a bond,    —OCH₂—, or —CH₂O—.-   16. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 12 wherein R4^(II) is a 5-membered    heteroaryl ring having 1, 2, or 3 optional substituents    independently chosen from —NH₂ or —NH(C1-C3) alkyl.-   17. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 12 wherein L₂ ^(II) is —CH₂— or —CH₂CH₂—.-   18. The use of any one of items 1-17 wherein said method of treating    or preventing is a method of treating or preventing cancer,    depression, a neurodegenerative disease or disorder, or a viral    infection.-   19. The use of item 17 wherein said neurodegenerative disease or    disorder is chosen from Alzheimer Disease, Parkinson Disease,    Huntington Disease, Frontotemporal Dementia or Amytrophic Lateral    Sclerosis.-   20. The use of item 17 wherein said neurodegenerative disease or    disorder is chosen from Alzheimer Disease, Parkinson Disease,    Huntington Disease, Frontotemporal Dementia or Amytrophic Lateral    Sclerosis.-   21. The use of item 17 wherein said neurodegenerative disease or    disorder is Alzheimer Disease.-   22. The use of item 17 wherein said neurodegenerative disease or    disorder is Parkinson Disease.-   23. The use of item 17 wherein said neurodegenerative disease or    disorder is Huntington Disease.-   24. The use of item 17 wherein said neurodegenerative disease or    disorder is Frontotemporal Dementia.-   25. The use of item 17 wherein said neurodegenerative disease or    disorder is Amytrophic Lateral Sclerosis.-   26. An optically active compound, or a pharmaceutically acceptable    salt or solvate thereof, of Formula (III):    R1^(III)-(A^(III))-R2^(III)    -   wherein (A^(III)) is an aryl or heteroaryl group having 2        substituents, R1^(III) and R2^(III), and 1 to 3 optional        substituents wherein said optional substituents are        independently chosen from halo, C1-C3 alkyl, or C1-C3 alkoxy;    -   R1^(III) is an -L₁ ^(III)-R3^(III) group;    -   R3^(III) is a phenyl, pyridyl, thiazolyl, or thienyl group        having 0, 1, 2, or 3 substituents independently chosen from —F,        —Cl, —OH, —NHSO₂R^(A), C1-C3 alkyl, C1-C3 alkoxy, cyano, —CF₃,        or —OCF₃ wherein R^(A) is C1-C6 alkyl or phenyl;    -   L₁ ^(III) is chosen from a bond, —CH₂O—, or —CH₂O—,    -   R2^(III) is -Cyclopropyl-NH-L₂ ^(III)-R4^(III) wherein said        cyclopropyl group has two chiral centers substituted in the        trans orientation corresponding to the carbons to which        (A^(III)) and —NH-L₂ ^(III)-R4^(III) are covalently attached;    -   R4^(III) is a 5-membered heteroaryl ring having 1, 2, or 3        optional substituents wherein said optional substituents are        independently chosen from —NH₂ or —NH(C1-C3) alkyl; and    -   L₂ ^(III) is —CH₂— or —CH₂CH₂—.-   27. The compound of item 26 wherein (A^(III)) is a phenyl or pyridyl    group.-   28. The compound of item 26 wherein R3^(III) is a phenyl having 0,    1, 2, or 3 substituents independently chosen from —F, —Cl, —OH,    —NHSO₂R^(A), C1-C3 alkyl, C1-C3 alkoxy, cyano, —CF₃, or —OCF₃    wherein R^(A) is C1-C6 alkyl or phenyl;-   29. The compound of item 26 wherein L₁ ^(III) is chosen from a bond,    —OCH₂—, or —CH₂O—,-   30. The compound of item 26 wherein R4^(III) is a 5-membered    heteroaryl ring wherein the chain of atoms comprising said    5-membered heteroaryl ring has 2 or 3 hetero atoms independently    chosen from N, S, or O and said heteroaryl ring has 1 optional    substituent wherein said optional substituent, if present, is —NH₂    or —NH(C1-C3) alkyl.-   31. The compound of item 26 wherein L₂ ^(III) is —CH₂— or —CH₂CH₂—.-   32. The compound of item 26 wherein R3^(III) is a phenyl having 0,    1, 2, or 3 substituents independently chosen from —F, —Cl, —OH,    —NHSO₂CH₃, methyl, methoxy, cyano, —CF₃, or —OCF₃.-   33. The compound of item 26 wherein R4^(III) is an oxadiazolyl,    thiadiazolyl, or thiazolyl ring having 1 optional substituent    wherein said optional substituent, if present, is —NH₂ or —NH(C1-C3)    alkyl.-   34. The compound of item 26 wherein R4^(III) is an oxadiazolyl ring    having 1 optional substituent chosen from —NH₂ or —NH(C1-C3) alkyl.-   35. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl cyclopropylamine rotates plane    polarized light in the (−) sense or is the (−) enantiomer.-   36. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine is 90% or greater    (−) stereoisomer and 10% or less (+) steroisomer.-   37. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of item 1 any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine is 95% or greater    (−) stereoisomer and 5% or less (+).-   38. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine 98% or greater    (−) stereoisomer and 2% or less (+).-   39. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine 99% or greater    (−) stereoisomer and 1% or less (+).-   40. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine-   99.5% or greater (−) stereoisomer and 0.5% or less (+).-   41. The optically active N-substituted aryl- or    heteroaryl-cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine has a 90% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   42. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine has a 95% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   43. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine has a 98% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   44. The optically active N-substituted aryl- or heteroaryl    cyclopropylamine of any one of items 26-34 wherein said    N-substituted aryl- or heteroaryl-cyclopropylamine has a 99% or more    enantiomeric excess of the (−) stereoisomer of the N-substituted    aryl- or heteroaryl-cyclopropylamine.-   45. A method of treatment or prevention of a disease or disorder    said method comprising administering to an individual in need of    said treatment or prevention an effective amount of an optically    active N-substituted aryl- or heteroaryl-cyclopropylamine or a    pharmaceutically acceptable salt or solvate thereof.-   46. The method of item 45 wherein said optically active    N-substituted aryl- or heteroaryl-cyclopropylamine is as in any one    of items 26-44.-   47. The method of item 45 or 46 wherein said disease or disorder is    chosen from cancer, a neurodegenerative disease or disorder, viral    infection, or depression.-   48. The method of item 45 or 46 wherein said disease or disorder is    a neurodegenerative disease or disorder chosen from Alzheimer    disease, Parkinson disease, Huntington Disease, Frontotemporal    Dementia, or Amytrophic Lateral Sclerosis.-   49. A optically active compound or a pharmaceutically acceptable    salt or solvate thereof wherein said optically active compound is    chosen from:-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;-   (−)    5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   (−)    N-(5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;    or-   (−)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine-   50. The compound of item 49 chosen from (−)    N-(5-((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;    (−)    5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;    or (−)    5-(((2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine.-   51. The compound of item 49 which is (−)    5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine.-   52. The compound of item 49 which is (−)    5-((((2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine.-   53. The compound of item 49 which is (−)    N-(5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide.-   54. A pharmaceutical composition comprising an optically active    compound as in any one of items 26-44 or 49 or a pharmaceutically    acceptable salt thereof, and a pharmaceutically acceptable carrier.-   55. The pharmaceutical composition of 54 for use in a method of    treating or preventing a disease or disorder.-   56. The pharmaceutical composition of item 55 wherein said disease    or disorder is a human disease or disorder chosen from cancer, a    neurological disease or disorder, or a viral infection.-   57. The pharmaceutical composition of item 56 where n said    neurological disease or disorder is depression or a    neurodegenerative disease or disorder.-   58. The pharmaceutical composition of item 57 wherein said    neurodegenerative disease or disorder is Alzheimer disease,    Parkinson disease, Huntington Disease, Frontotemporal Dementia, or    Amytrophic Lateral Sclerosis.-   59. An optically active compound chosen from:-   (+)    5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;-   (+)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;-   (+)    N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;-   (+)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine;    or-   (+)    5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;    or a pharmaceutical acceptable salt or solvate thereof.-   60. A method for enriching an enantiomer of a trans N-substituted    cyclopropylamine comprising: contacting a trans-substituted    cyclopropylamine with a chiral recrystallization agent in a solvent    and under conditions are sufficient for the crystallization for the    salt of the chiral recrystallization agent and the trans substituted    cylopropylamine; and isolating the crystallized salt of the chiral    recrystallization agent and the trans substituted cyclopropylamine.-   61. The method of item 60 wherein the trans cyclopropylamine is    trans 4-benzoxy-2-phenylcyclopropylamine or a protected derivative    thereof.-   62. The method of item 60 wherein the chiral recrystallization agent    is chosen from S (+) mandelic acid, D (−) tartaric acid, L (−)    di-p-tolyl tartaric acid, or R (−) mandelic acid.-   63. The method of item 60 or 61 wherein the chiral recrystallization    agent is R (−) mandelic acid.-   64. The method of item 60, 61, 62, or 63 wherein the solvent is THF    and H₂O.

DEFINITIONS

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

As used herein, the term “acyl,” refers to a carbonyl attached to analkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any othermoiety where the atom attached to the carbonyl is carbon. An “acetyl”group refers to a —C(═O)CH₃ group. An “alkylcarbonyl” or “alkanoyl”group refers to an alkyl group attached to the parent molecular moietythrough a carbonyl group. Examples of such groups include, but are notlimited to, methylcarbonyl or ethylcarbonyl. Examples of acyl groupsinclude, but are not limited to, formyl, alkanoyl or aroyl.

As used herein, the term “alkenyl,” refers to a straight-chain orbranched-chain hydrocarbon group having one or more double bonds andcontaining from 2 to 20 carbon atoms. A (C2-C6)alkenyl has from 2 to 6carbon atoms.

As used herein, the term “alkoxy,” refers to an alkyl ether group,wherein the term alkyl is as defined below. Examples of suitable alkylether groups include, but are not limited to, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, orn-pentoxy.

As used herein, the term “alkyl,” refers to a straight-chain orbranched-chain alkyl group containing from 1 to 20 carbon atoms. A(C1-C10)alkyl has from 1 to 10 carbon atoms and a (C1-C6)alkyl has from1 to 6 carbon atoms and a (C1-C4)alkyl has from 1 to 4 carbon atoms.Examples of alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neo-pentyl, iso-amyl, hexyl, heptyl, octyl, or nonyl.

As used herein, the term “alkylene” refers to an alkyl group attached attwo positions, i.e. an alkanediyl group. Examples include, but are notlimited to, methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene, or nonylene. Accordingly, the term“alkylene” may, e.g., refer to a straight-chain or branched-chainalkylene group having from 1 to 6 carbon atoms.

As used herein, the term “alkylamino,” refers to an alkyl group attachedto the parent molecular moiety through an amino group. Suitablealkylamino groups may be mono- or dialkylated, forming groups including,but not limited to N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-ethylmethylamino, N,N-diethylamino, N-propyl amino, andN,N-methylpropylamino.

As used herein, the term “alkynyl,” refers to a straight-chain orbranched-chain hydrocarbon group having one or more triple bonds andcontaining from 2 to 20 carbon atoms. A (C2-C6)alkynyl has from 2 to 6carbon atoms. A (C2-C4)alkynyl has from 2 to 4 carbon atoms. Examples ofalkynyl groups include, but are not limited to, ethynyl, propynyl,hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl,3-methylbutyn-1-yl, or hexyn-2-yl.

As used herein, the terms “amido” and “carbamoyl,” refer to an aminogroup as described below attached to the parent molecular moiety througha carbonyl group (e.g., —C(═O)NRR′), or vice versa (—N(R)C(═O)R′).“Amido” and “carbamoyl” encompass “C-amido”, “N-amido” and “acylamino”as defined herein. R and R′ are as defined herein.

As used herein, the term “C-amido,” refers to a —C(═O)NRR′ group with Rand R′ as defined herein.

As used herein, the term “amino,” refers to —NRR′, wherein R and R′ areindependently selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl, carbocyclyl, and heterocyclyl, Additionally, R and R′may be combined to form a heterocyclyl.

As used herein, the term “aryl,” refers a carbocyclic aromatic systemcontaining one ring, or two or three rings fused together where in thering atoms are all carbon. The term “aryl” groups includes, but is notlimited to groups such as phenyl, naphthyl, or anthracenyl.

As used herein, the term “arylalkoxy” or “aralkoxy,” refers to an arylgroup attached to the parent molecular moiety through an alkoxy group.Examples of arylalkoxy groups include, but are not limited to, benzyloxyor phenethoxy.

As used herein, the term “arylalkyl” or “aralkyl,” refers to an arylgroup attached to the parent molecular moiety through an alkyl group.

As used herein, the term “aryloxy,” refers to an aryl group attached tothe parent molecular moiety through an oxy (—O—).

As used herein, the term “carbamate,” refers to an O-carbamyl orN-carbamyl group as defined herein.

As used herein, the term “carbonyl,” when alone includes formyl —C(═O)Hand in combination is a —C(═O)— group.

As used herein, the term “carboxyl” or “carboxy” refers to —C(═O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(═O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(═O)OR groups where Ris as defined herein.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “carbocyclyl” refers to a saturated orpartially saturated monocyclic or a fused bicyclic or tricyclic groupwherein the ring atoms of the cyclic system are all carbon and whereineach cyclic moiety contains from 3 to 12 carbon atom ring members.“Carbocyclyl” encompasses benzo fused to a carbocyclyl ring system. Onegroup of carbocyclyls have from 5 to 7 carbon atoms. Examples ofcarbocyclyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, or adamantyl.

As used herein, the term “cycloalkyl” refers to a saturated monocyclic,bicyclic or tricyclic group wherein the ring atoms of the cyclic systemare all carbon and wherein each cyclic moiety contains from 3 to 12carbon atom ring members. One group of cycloalkyls has from 5 to 7carbon atoms. Examples of cycloalkyl groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oradamantyl.

As used herein, the term “cycloalkenyl” refers to a partially saturatedmonocyclic, bicyclic or tricyclic group wherein the ring atoms of thecyclic system are all carbon and wherein each cyclic moiety containsfrom 3 to 12 carbon atom ring members. One group of carboalkenyls havefrom 5 to 7 carbon atoms. Examples of cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, or cyclohexenyl.

As used herein, the term “cyclyl” refers to an aryl, heterocyclyl, orcarbocyclyl group as defined herein.

As used herein, the term “halo” or “halogen” refers to fluorine,chlorine, bromine, or iodine.

As used herein, the term “haloalkoxy” refers to a haloalkyl groupattached to the parent molecular moiety through an oxygen atom. Examplesof haloalkoxy groups include, but are not limited to, trifluoromethoxy,2-fluoroethoxy, or 3-chloropropoxy.

As used herein, the term “haloalkyl” refers to an alkyl group having themeaning as defined above wherein one or more hydrogens are replaced witha halogen. Specifically embraced are monohaloalkyl, dihaloalkyl orpolyhaloalkyl groups. A monohaloalkyl group, for one example, may havean iodo, bromo, chloro or fluoro atom within the group. Dihalo orpolyhaloalkyl groups may have two or more of the same halo atoms or acombination of different halo groups. Examples of haloalkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl ordichloropropyl.

As used herein, the term “heteroalkyl” refers to a straight or branchedalkyl chain, wherein one, two, or three carbons forming the alkyl chainare each replaced by a heteroatom independently selected from the groupconsisting of O, N, and S, and wherein the nitrogen and/or sulfurheteroatom(s) (if present) may optionally be oxidized and the nitrogenheteroatom(s) (if present) may optionally be quaternized. Theheteroatom(s) O, N and S may, for example, be placed at an interiorposition of the heteroalkyl group, i.e., the heteroalkyl may be bound tothe remainder of the molecule via a carbon atom. Up to two heteroatomsmay be consecutive, such as, for example, —CH₂—NH—OCH₃. Accordingly, afurther example for a “heteroalkyl” group is a straight or branchedalkyl group, in which two consecutive carbon atoms are replaced by theheteroatoms S and N, respectively, and the sulfur heteroatom isfurthermore oxidized, resulting in moieties such as, e.g., —S(═O)₂—NH₂,—S(═O)₂—NH(alkyl) or —S(═O)₂—N(alkyl)(alkyl).

As used herein, the tee “heteroalkylene” refers to a heteroalkyl groupattached at two positions. Examples include, but are not limited to,—CH₂OCH₂—, —CH₂SCH₂—, and —CH₂NHCH₂—, —CH₂S—, or —CH₂NHCH(CH₃)CH₂—.Accordingly, the term “heteroalkylene” may, e.g., refer to a straight orbranched alkylene group (i.e., a straight or branched alkanediyl group)having from 1 to 6 carbon atoms, wherein 1, 2 (if present) or 3 (ifpresent) of said carbon atoms are each replaced by a heteroatomindependently selected from O, N or S. It is to be understood that thepresence of hydrogen atoms will depend on the valence of the heteroatomreplacing the respective carbon atom. If, for example, the carbon atomin a —CH₂— group is replaced by O or S, the resulting group will be —O—or —S—, respectively, while it will be —N(H)— when the carbon atomreplaced by N. Likewise, if the central carbon atom in a group—CH₂—CH(—CH₃)—CH₂— is replaced by N, the resulting group will be—CH₂—N(—CH₃)—CH₂—. An example for a “heteroalkylene” group is a straightor branched alkylene group, in which two consecutive carbon atoms arereplaced by the heteroatoms S and N, respectively, and the sulfurheteroatom is furthermore oxidized, resulting in moieties such as, e.g.,—S(═O)₂—N(H)— or —S(═O)₂—N(alkyl)-. Accordingly, the groups—S(═O)₂—N(H)— and —S(═O)₂—N(alkyl)- (e.g., —S(═O)₂—N(C₁-C₆ alkyl)-) areexemplary “heteroalkylene” groups.

As used herein, the term “heteroaryl,” refers to a 3 to 7 memberedunsaturated monocyclic ring, or a fused monocyclic, bicyclic, ortricyclic ring system in which the rings are aromatic and which at leastone ring contains at least one atom selected from the group consistingof O, S, and N. One group of heteroaryls has from 5 to 7 carbon atoms.Examples of heteroaryl groups include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, or furopyridinyl.

As used herein, the term “heterocyclyl” or “heterocycle,” each refer toa saturated, partially unsaturated, or fully unsaturated monocyclic,bicyclic, or tricyclic heterocyclic group containing at least oneheteroatom as a ring member, wherein each said heteroatom may beindependently selected from the group consisting of nitrogen, oxygen,and sulfur wherein the nitron or sulfur atoms may be oxidized (e.g.,—N═O, —S(═O)—, or —S(═O)₂—). Additionally, 1, 2, or 3 of the carbonatoms of the heterocyclyl may be optionally oxidized (e.g., to give anoxo group or ═O). One group of heterocyclyls has from 1 to 4 heteroatomsas ring members. Another group of heterocyclyls has from 1 to 2heteroatoms as ring members. One group of heterocyclyls has from 3 to 8ring members in each ring. Yet another group of heterocyclyls has from 3to 7 ring members in each ring. Again another group of heterocyclyls hasfrom 5 to 6 ring members in each ring. “Heterocyclyl” is intended toencompass a heterocyclyl group fused to a carbocyclyl or benzo ringsystems. Examples of heterocyclyl groups include, but are not limitedto, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examplesof heteroaryls that are heterocyclyls include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, or furopyridinyl.

As used herein, the term “heterocycloalkyl,” refers to a heterocyclylgroup that is not fully saturated e.g., one or more of the rings systemsof a heterocycloalkyl is not aromatic. Examples of heterocycloalkylsinclude piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl.

As used herein, the term “hydroxyl,” as used herein, refers to —OH.

As used herein, the term “hydroxyalkyl,” as used herein, refers to ahydroxyl group attached to the parent molecular moiety through an alkylgroup.

As used herein, the phrase “in the main chain,” refers to the longestcontiguous or adjacent chain of carbon atoms starting at the point ofattachment of a group to the compounds of any one of the formulasdisclosed herein.

As used herein, the term phrase “linear chain of atoms” refers to thelongest straight chain of atoms independently selected from carbon,nitrogen, oxygen and sulfur.

As used herein, the term “lower,” where not otherwise specificallydefined, means containing from 1 to and including 6 carbon atoms.

As used herein, the term “lower aryl,” means phenyl or naphthyl.

As used herein, the term “lower heteroaryl,” means either 1) monocyclicheteroaryl comprising five or six ring members, of which between one andfour said members may be heteroatoms selected from O, S, or N.

As used herein, the term “nitro,” refers to —NO₂.

As used herein, the terms “sulfonate” “sulfonic acid” and “sulfonic,”refers to the —SO₃H group and its anion as the sulfonic acid is used insalt formation.

As used herein, the term “sulfanyl,” to —S—.

As used herein, the term “sulfinyl,” refers to —S(═O)(R)—, with R asdefined herein.

As used herein, the term “sulfonyl,” refers to —S(═O)₂R, with R asdefined herein.

As used herein, the term “sulfonamide”, refers to an N-sulfonamido orS-sulfonamido group as defined herein.

As used herein, the term “N-sulfonamido,” refers to a RS(═O)₂N(R′)—group with R and R′ as defined herein. Exemplary, non-limitingN-sulfonamido groups are —NHSO₂CH₃, —NHSO₂CH₂CH₃, —NHSO₂(phenyl), or—NHSO₂(isopropyl).

As used herein, the term “S-sulfonamido,” refers to a —S(═O)₂NRR′,group, with R and R as defined herein.

As used herein, the term “urea,” refers to a —N(R)C(═O)N(R) groupwherein R and R′ are as defined herein.

As used herein, “hydrogen bonding group” refers to a substituent group,which is capable of taking part in a non-covalent bonding betweenhydrogen and another atom (usually nitrogen or oxygen). Examplesinclude, but are not limited to, —NH₂, —OH, amido, —S(O)₂NH₂, —C(═O)NH₂,—CH₂—C(═O)NH₂, - and —CH₂—NH₂. Other non-limiting examples includeNHC(═O)CH₃ or —NHCH₃.

As used herein, the term “amide isostere” refers to a monocyclic orbicyclic ring system that is isosteric or bioisosteric with an amidemoiety. Examples of amide isoteres include but are not limited to thosedisclosed in, e.g., Meanwell (2011) J. Med. Chem. PMID: 21413808,

As used herein, the term “optionally substituted” means the preceding oranteceding group may be substituted or unsubstituted. When substituted,the substituents of an “optionally substituted” group may include,without limitation, one or more substituents independently selected fromthe following groups or a particular designated set of groups, alone orin combination: lower alkyl, lower alkenyl, lower alkynyl, loweralkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl,lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy,oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lowercarboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxyl,amino, lower alkylamino, arylamino, aminoalkyl, amido, nitro, thiol,lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio,sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃,CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, carbamate, and urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.” In one specific definition, the optionalsubstituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl,haloalkoxy, —N((C1-C3)alkyl)₂, —NH((C1-C3)alkyl),—NHC(═O)((C1-C3)alkyl), —C(═O)OH, —C(═O)O((C1-C3)alkyl),—C(═O)(C1-C3)alkyl), —C(═O)NH₂, —C(═O)NH(C1-C3)alkyl),—C(═O)NH(cycloalkyl), —C(═O)N(C1-C3)alkyl)₂, —S(═O)₂((C1-C3)alkyl),—S(═O)₂NH₂, —S(═O)₂N((C1-C3)alkyl)₂, —S(═O)₂NH((C1-C3)alkyl), —CHF₂,—OCF₃, —OCHF₂, —SCF₃, —CF₃, —CN, —NH₂, —NO₂, or tetrazolyl.

As used herein, the term “optional substituent” denotes that thecorresponding substituent may be present or may be absent. Accordingly,a compound having 1, 2 or 3 optional substituents may be unsubstitutedor may be substituted with 1, 2 or 3 substituents.

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl, Whether an R group has a numberdesignation or not, every R group, including R, R′ and R^(p) where p=(1,2, 3, . . . p), every substituent, and every term should be understoodto be independent of every other in terms of selection from a group.Should any variable, substituent, or term (e.g., aryl, heterocycle, R,etc.) occur more than one time in a formula or generic structure, itsdefinition at each occurrence is independent of the definition at everyother occurrence. Those of skill in the art will further recognize thatcertain groups may be attached to a parent molecule or may occupy aposition in a chain of elements from either end as written. Thus, by wayof example only, an unsymmetrical group such as —C(═O)N(R)— may beattached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

As used herein, the term “optically active,” refers to the ability of acompound to rotate plane polarized light. In the context of theinvention, the term refers to mixtures of enantiomers which are notracemic mixtures; that is to say, not a 50:50 mixture of a (+)enantiomer and the corresponding (−) enantiomer.

As used herein, the term “N-substituted aryl orheteroarylcyclopropylamine” (or, likewise, “N-substituted aryl- orheteroaryl-cyclopropylamine”), refers to a compound having a 1,2disubstituted cyclopropyl core wherein the 1 and 2 positions aresubstituted with an substituted amine group and a substituted aryl orheteroaryl group. Compounds of Formula (II) and Formula (III) asdescribed herein are examples of N-substituted aryl- orheteroaryl-cyclopropylamines.

As used herein, the term “enantiomeric excess” or “ee” or “percentenantiomeric excess” refers to the difference between the mole fractionof one specific enantiomer (i.e., the specified enantiomer) and the molefraction of the other enantiomer in relation to the sum of the molefractions of both enantiomers, expressed as a percent value, and thusdescribes the extent of the excess of one specific enantiomer inrelation to the other enantiomer. If, for example, a specific enantiomeris provided in the absence of the other enantiomer, the enantiomericexcess will be 100%, while a racemate comprising equal molar amounts ofthe two enantiomers will have an enantiomeric excess of 0%. Accordingly,the “enantiomeric excess” or “ee” or “percent enantiomeric excess” isdefined by the following formula:

$\frac{\begin{matrix}{\left( {{mole}\mspace{14mu}{fraction}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{specified}\mspace{14mu}{enantiomer}} \right) -} \\\left( {{mole}\mspace{14mu}{fraction}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{other}\mspace{14mu}{enantiomer}} \right)\end{matrix}}{\begin{matrix}{\left( {{mole}\mspace{14mu}{fraction}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{specified}\mspace{14mu}{enantiomer}} \right) +} \\\left( {{mole}\mspace{14mu}{fraction}\mspace{14mu}{of}\mspace{14mu}{the}\mspace{14mu}{other}\mspace{14mu}{enantiomer}} \right)\end{matrix}} \cdot 100$

As used herein, the term “preventing an increase in a symptom,” refersto both not allowing a symptom to increase or worsen, as well asreducing the rate of increase in the symptom. For example, a symptom canbe measured as the amount of particular disease marker, i.e., a protein(e.g., cancer biomarker). In another example the symptom can becognitive decline. Preventing an increase, according to the definitionprovided herein, means that the amount of symptom (e.g., protein orcognitive decline) does not increase or that the rate at which itincreases is reduced.

As used herein, the term “treating a disease or disorder,” refers to aslowing of or a reversal of the progress of the disease. Treating adisease or disorder includes treating a symptom and/or reducing thesymptoms of the disease.

As used herein, the term “preventing a disease or disorder,” refers to aslowing of the disease or of the onset of the disease or the symptomsthereof. Preventing a disease or disorder can include stopping the onsetof the disease or symptoms thereof. As used herein, the term “unitdosage form” refers to a physically discrete unit, such as a capsule ortablet suitable as a unitary dosage for a human patient. Each unitcontains a predetermined quantity of a compound of Formula (I), (Ia),(Ib), (II) or (III) which was discovered or believed to produce thedesired pharmacokinetic profile which yields the desired therapeuticeffect. The dosage unit is composed of a compound of Formula (I), (Ia),(Ib), (II) or (III) in association with at least one pharmaceuticallyacceptable carrier, salt, excipient, or combination thereof.

As used herein, the term “subject” or “patient” or “individual”, such asthe subject in need of treatment or prevention, may be a eukaryote, ananimal, a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, ahamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., adog), a feline (e.g., a cat), an equine (e.g. a horse), a primate, asimian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon),an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human. Themeaning of the terms “eukaryote”, “animal”, “mammal”, etc. is well knownin the art and can, for example, be deduced from Wehner and Gehring(1995; Thieme Verlag). In the context of this invention, it isparticularly envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Lower organisms such as, e.g., fruit flies like Drosophilamelagonaster and nematodes like Caenorhabditis elegans may also be usedin scientific approaches. Non-limiting examples of agronomicallyimportant animals are sheep, cattle and pig, while, for example, catsand dogs may be considered as economically important animals.Preferably, the subject/patient/individual is a mammal; more preferably,the subject/patient/individual is a human or a non-human mammal (suchas, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, acat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, achimpanzee, an orangutang, a gibbon, a sheep, cattle, or a pig); evenmore preferably, the subject/patient/individual is a human.

As used herein, the term “dose” or “dosage,” refers the amount of activeingredient that an individual takes or is administered at one time. Forexample, a 40 mg dose of a compound of Formula (I), (Ia), (Ib), (II) or(III) refers to, in the case of a twice-daily dosage regimen, asituation where the individual takes 40 mg of a compound of Formula (I)twice a day, e.g., 40 mg in the morning and 40 mg in the evening. The 40mg of a compound of Formula (I), (Ia), (Ib), (II) or (III) dose can bedivided into two or more dosage units, e.g., two 20 mg dosage units of acompound of Formula (I), (Ia), (Ib), (II) or (III) in tablet form or two20 mg dosage units of a compound of Formula (I), (Ia), (Ib), (II) or(III) in capsule form.

As used herein, a “pharmaceutically acceptable prodrug” is a compoundthat may be converted under physiological conditions or by solvolysis tothe specified compound or to a pharmaceutically acceptable salt of suchcompound.

As used herein, a “pharmaceutically active metabolite” is intended tomean a pharmacologically active product produced through metabolism inthe body of a specified compound or salt thereof. Metabolites of acompound may be identified using routine techniques known in the art andtheir activities determined using tests such as those described herein.

As used herein, a “pharmaceutically acceptable salt” is intended to meana salt that retains the biological effectiveness of the free acids andbases of the specified compound and that is not biologically orotherwise undesirable. A compound for use in the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Exemplary pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid or an inorganic base, such assalts including sulfates, pyrosulfates, bisulfates, sulfites,bisulfites, phosphates, monohydrophosphates, dihydrophosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4 dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,glycollates, tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, or mandelates.

As used herein, a “pharmaceutically acceptable carrier” refers to anon-API (API refers to Active Pharmaceutical Ingredient) substances suchas disintegrators, binders, fillers, and lubricants used in formulatingpharmaceutical products. They are generally safe for administering tohumans according to established governmental standards, including thosepromulgated by the United States Food and Drug Administration and theEuropean Medical Agency.

As is understood by the skilled artisan, certain variables in the listof substituents are repetitive (different name for the samesubstituent), generic to other terms in the list, and/or partiallyoverlap in content with other terms. In the compounds of the invention,the skilled artisan recognizes that substituents may be attached to theremainder of the molecule via a number of positions and the preferredpositions are as illustrated in the Examples.

As described herein above, the compound of Formula (I), (Ia) or (Ib)contains asymmetric carbon atoms and can therefore exist in racemic andoptically active forms. Thus, optical isomers or enantiomers, racemates,tautomers, and diastereomers are also encompassed by the compounds ofFormula (I), (Ia) or (Ib). The methods of the present invention includethe use of all such isomers and mixtures thereof. Methods of separationof enantiomeric and diastereomeric mixtures are well known to oneskilled in the art and are furthermore described in the appendedexamples. The present invention encompasses any isolated racemic oroptically active form of compounds according to Formula (I), (Ia) or(Ib), or any mixture thereof. In one aspect, the compounds of theinvention have a trans configuration around the cyclopropyl ring as intrans-phenylcyclopropylamine. In one aspect, the compounds of theinvention have a cis configuration around the cyclopropyl ring as incis-phenylcyclopropylamine. In a preferred aspect, the compounds ofFormula (I), (Ia) or (Ib) have the trans configuration. In a morepreferred aspect, the compounds of Formula (I), (Ia) or (Ib) are (−)stereoisomers having the trans configuration around the cyclopropylring.

Typically, compounds according to Formula (I), (Ia), (Ib), (II) or (III)can be effective at an amount of from about 0.01 μg/kg to about 100mg/kg per day based on total body weight. The active ingredient may beadministered at once, or may be divided into a number of smaller dosesto be administered at predetermined intervals of time. The suitabledosage unit for each administration can be, e.g., from about 1 μg toabout 2000 mg, preferably from about 5 μg to about 1000 mg. Even morepreferably, the amount of active ingredient administered is from about 5μg to about 100 mg per day. These doses will depend of thepharmacokinetic parameters of the particular compound and other ADMEproperties as well as the efficacy of the compound in a particulardisease setting.

It should be understood that the dosage ranges set forth above areexemplary only and are not intended to limit the scope of thisinvention. The therapeutically effective amount for each active compoundcan vary with factors including but not limited to the activity of thecompound used, stability of the active compound in the patient's body,the severity of the conditions to be alleviated, the total weight of thepatient treated, the route of administration, the ease of absorption,distribution, and excretion of the active compound by the body, the ageand sensitivity of the patient to be treated, and the like, as will beapparent to a skilled artisan. The amount of administration can beadjusted as the various factors change over time.

For oral delivery, the active compounds can be incorporated into aformulation that includes pharmaceutically acceptable carriers such asbinders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,starch, lactose), lubricants (e.g., magnesium stearate, silicondioxide), disintegrating agents (e.g., alginate, Primogel, and cornstarch), and sweetening or flavoring agents (e.g., glucose, sucrose,saccharin, methyl salicylate, and peppermint). The formulation can beorally delivered in the form of enclosed gelatin capsules or compressedtablets. Capsules and tablets can be prepared in any conventionaltechniques. The capsules and tablets can also be coated with variouscoatings known in the art to modify the flavors, tastes, colors, andshapes of the capsules and tablets. In addition, liquid carriers such asfatty oil can also be included in capsules.

Suitable oral formulations can also be in the form of suspension, syrup,chewing gum, wafer, elixir, and the like. If desired, conventionalagents for modifying flavors, tastes, colors, and shapes of the specialforms can also be included. In addition, for convenient administrationby enteral feeding tube in patients unable to swallow, the activecompounds can be dissolved in an acceptable lipophilic vegetable oilvehicle such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally in the formof solution or suspension, or in lyophilized form capable of conversioninto a solution or suspension form before use. In such formulations,diluents or pharmaceutically acceptable carriers such as sterile waterand physiological saline buffer can be used. Other conventionalsolvents, pH buffers, stabilizers, anti-bacteria agents, surfactants,and antioxidants can all be included. For example, useful componentsinclude sodium chloride, acetates, citrates or phosphates buffers,glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol,propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, andthe like. The parenteral formulations can be stored in any conventionalcontainers such as vials and ampoules.

Routes of topical administration include nasal, bucal, mucosal, rectal,or vaginal applications. For topical administration, the activecompounds can be formulated into lotions, creams, ointments, gels,powders, pastes, sprays, suspensions, drops and aerosols. Thus, one ormore thickening agents, humectants, and stabilizing agents can beincluded in the formulations. Examples of such agents include, but arenot limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,beeswax, or mineral oil, lanolin, squalene, and the like. A special formof topical administration is delivery by a transdermal patch. Methodsfor preparing transdermal patches are disclosed, e.g., in Brown, et al.(1988) Ann. Rev. Med. 39:221-229 which is incorporated herein byreference.

Subcutaneous implantation for sustained release of the active compoundsmay also be a suitable route of administration. This entails surgicalprocedures for implanting an active compound in any suitable formulationinto a subcutaneous space, e.g., beneath the anterior abdominal wall.See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogelscan be used as a carrier for the sustained release of the activecompounds. Hydrogels are generally known in the art. They are typicallymade by crosslinking high molecular weight biocompatible polymers into anetwork, which swells in water to form a gel like material. Preferably,hydrogels are biodegradable or biosorbable. For purposes of thisinvention, hydrogels made of polyethylene glycols, collagen, orpoly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips etal. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

The active compounds can also be conjugated, to a water solublenon-immunogenic non-peptidic high molecular weight polymer to form apolymer conjugate. For example, an active compound is covalently linkedto polyethylene glycol to form a conjugate. Typically, such a conjugateexhibits improved solubility, stability, and reduced toxicity andimmunogenicity. Thus, when administered to a patient, the activecompound in the conjugate can have a longer half-life in the body, andexhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp.Pharm. 15:210-218. PEGylated proteins are currently being used inprotein replacement therapies and for other therapeutic uses. Forexample, PEGylated interferon (PEG-INTRON A®) is clinically used fortreating Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is beingused to treat severe combined immunodeficiency disease (SCIDS).PEGylated L-asparaginase (ONCAPSPAR®) is being used to treat acutelymphoblastic leukemia (ALL). It is preferred that the covalent linkagebetween the polymer and the active compound and/or the polymer itself ishydrolytically degradable under physiological conditions. Suchconjugates known as “prodrugs” can readily release the active compoundinside the body. Controlled release of an active compound can also beachieved by incorporating the active ingredient into microcapsules,nanocapsules, or hydrogels generally known in the art. Otherpharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters.

Liposomes can also be used as carriers for the active compounds of thepresent invention. Liposomes are micelles made of various lipids such ascholesterol, phospholipids, fatty acids, and derivatives thereof.Various modified lipids can also be used. Liposomes can reduce thetoxicity of the active compounds, and increase their stability. Methodsfor preparing liposomal suspensions containing active ingredientstherein are generally known in the art. See, e.g., U.S. Pat. No.4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.Y. (1976).

The active compounds can also be administered in combination withanother active agent that synergistically treats or prevents the samesymptoms or is effective for another disease or symptom in the patienttreated so long as the other active agent does not interfere with oradversely affect the effects of the active compounds of this invention.Such other active agents include but are not limited toanti-inflammation agents, antiviral agents, antibiotics, antifungalagents, antithrombotic agents, cardiovascular drugs, cholesterollowering agents, anti-cancer drugs, hypertension drugs, and the like.

Examples of antineoplastic agents that can be used in combination withthe compounds and methods of the present invention include, in general,and as appropriate, alkylating agents, anti-metabolites,epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents and haematopoietic growthfactors. Exemplary classes of antineoplastic include the anthracyclines,vinca drugs, mitomycins, bleomycins, cytotoxic nucleosides, epothilones,discodermolides, pteridines, diynenes and podophyllotoxins. Particularlyuseful members of those classes include, for example, caminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin orpodo-phyllotoxin derivatives such as etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, paclitaxel and the like. Other useful antineoplastic agentsinclude estramustine, carboplatin, cyclophosphamide, bleomycin,gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa,cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase,camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

General Synthetic Route Description

Compounds of Formula (I), (Ia), (Ib), (II) or (III) can be synthesizedin accordance with or in analogy to the general routes described inSchemes 1, 2 and 3. Other routes known by the ordinary skilled artisan,as well as other reactants and intermediates, can also be used to arriveat the compounds of Formula (I), (Ia), (Ib), (II) or (III).

Commercially available nitrostyrenes of formula (1) have been subjectedto a cyclopropanation reaction using trimetilsulfoxonium iodide andpotassium tertbutylate. The nitro group of the resulted transnitrocyclopropyl derivatives of formula (2) (being trans ((1S, 2R), (1R,2S)) mixture although the individual diastereoisomers corresponding to(1S, 2R) and (1R, 2S) can be used) has been then reduced using zinc inhydrochloric acid to afford the cyclopropylamino derivatives of formula(3). Later reductive alkylation with commercially available aldehydes offormula (4) using sodium triacetoxyborohydride as reducing agent leadsto the formation of cyclopropylamino derivatives of formula (5) whichare subjects of the present invention.

Commercially availables aldehydes of formula (6) were subjected to aHorner-Wadsworth-Emmons reaction using triethyl phosphono acetate andpotassium tert-butoxide in tetrahydrofuran at 0° C. to get the ethylacrylate derivatives of formula (7) which is subjected tocyclopropanation using trimetilsulfoxonium iodide and sodium hydride indimethyl sulfoxide as a solvent, leading to (trans)-ethylcyclopropanecarboxylate derivatives of formula (8) (being trans ((1S,2R), (1R, 2S)) mixture although the individual diastereoisomerscorresponding to (1S, 2R) and (1R, 2S) can be used). Hydrolysis to thecorresponding (trans)-cyclopropanecarboxylic acid derivatives of formula(9) was performed using NaOH in MeOH. Reaction, first with ethylchloroformate and triethylamine in acetone and later with sodium azidein water leads to the formation of (trans)-cyclopropanecarbonyl azidederivatives of formula (10). Reaction with tert-butanol results in theformation of tert-butyl (trans)-cyclopropylcarbamate derivatives offormula (11). The reaction with commercially available boronic acid orboronate ester derivatives of formula (12) using acetonitrile and wateras a solvent, potassium carbonate as a base andTetrakis(triphenylphospine) Paladium (0) as a catalyst leads to theformation of tert-butyl (trans)-cyclopropylcarbamate derivatives offormula (13).

Deprotection of the Boc-group using HCl 2M in diethyl ether usingdiethyl ether as a solvent leads to the formation of the correspondinghydrochloride salt of the (trans)-cyclopropanamine derivatives offormula (9). Reductive alkylation with commercially available aldehidesof formula (4) using sodium triacetoxyborohydride as reducing agentleads to the formation of cyclopropylamino derivatives of formula (5)which are subjects of the present invention.

The alkylation of tert-butyl (trans)-cyclopropylcarbamate derivatives offormula (13) with commercial available alkyl halides of formula (14)using sodium hydride as a base and DMF as a solvent leads to theformation of the tert-butyl (trans)-cyclopropylcarbamate derivatives offormula (15). Deprotection of the Boc-group using HCl 2M in diethylether using diethyl ether as a solvent results in the formation of thecorresponding hydrochloride salt of the (trans)-cyclopropanaminederivatives of formula (5), which are subject of the present inventionas defined above.

The alkylation of commercially available aldehydes of formula (16) usingcommercially available alkyl halides of formula (17), potassiumcarbonate in N,N-dimethylformamide leads to the formation of thealdehyde derivatives of formula (18). A Horner-Wadsworth-Emmons reactionusing triethyl phosphono acetate and potassium tert-butoxide intetrahydrofuran at 0° C. gives the ethyl acrylate derivatives of formula(19) which are subjected to cyclopropanation using trimetilsulfoxoniumiodide and sodium hydride in dimethyl sulfoxide as a solvent leading to(trans)-ethyl cyclopropanecarboxylate derivatives of formula (20).Hydrolysis to the corresponding (trans)-cyclopropanecarboxylic acidderivatives of formula (21) was performed using NaOH in MeOH. Reaction,first with ethyl chloroformate and triethylamine in acetone and laterwith sodium azide in water leads to the formation of(trans)-cyclopropanecarbonyl azide derivatives of formula (22). Reactionwith tert-butanol results in the formation of tert-butyl(trans)-cyclopropylcarbamate derivatives of formula (23). Boc-groupdeprotection using HCl 2M in diethyl ether and diethyl ether as asolvent leads to the formation of the corresponding hydrochloride saltof the (trans)-cyclopropanamine derivatives of formula (24).

Reductive alkylation with commercially available aldehydes of formula(4) using sodium triacetoxyborohydride as a reducing agent leads to theformation of (trans)-cyclopropylamino derivatives of formula (25) whichare also subjects of the present invention.

Alternatively, alkylation of (trans)-cyclopropanamine derivatives offormula (24) with commercial available alkyl halides of formula (14)using potassium carbonate as a base and N,N-dimethylformamide as asolvent also leads to the formation of (trans)-cyclopropylaminoderivatives of formula (25), which are subject of the present inventionas defined above.

As known by those skilled in the art, (trans)-cyclopropylaminoderivatives of formula (5) and (25) can also be obtained from the(trans)-cyclopropanamine derivatives of formula (3) and (24),respectively, by a well-known reactions (i.e, cyclization).

Optically pure or enantiomerically enriched compounds can be isolated atvarious stages of the synthetic procedure and can be used in subsequentsteps.

EXAMPLES

The program used to generate the names corresponding to the structuresin the Example compounds below was ChemBioDraw Ultra 11.0.1. Thisprogram named the molecules as the (1S,2R) configuration due to theconfiguration of the input structure and the “trans” term has beensubstituted in the place of the (1S,2R) term specified by the program.The structures depicted below for the Example compounds below are shownas having one particular stereochemical configuration around thecyclopropyl carbon atoms of the phenylcyclopropylamine core (1S, 2R).Unless stated otherwise, the compounds synthesized in the Examples aremixtures having both configurations (1R, 2S) and (1S, 2R), that is tosay they are “trans” in respect to the substituents on the cyclopropylring system. This is due to the fact the cyclopropyl derivatives used asstarting material are “trans”. It is contemplated that the cisconfiguration starting material or the individual diastereomers could beused as starting material, all of which are either commercially orsynthetically available. Thus, the invention relates to compounds ofFormula (I), (Ia), (Ib), (II) or (III), including those of the examples,that have specific stereochemical configurations around the cyclopropylring e.g., trans ((1R, 2S) and (1S, 2R)) and cis ((1R, 2R) and (1S,2S)). A preferred stereochemical configuration around the cyclopropylring is trans.

The compounds of the examples can also be synthesized or provided in asalt form. The skilled artisan is aware and capable of making salt formsand/or converting salt forms of the compounds of the invention, e.g.,compounds of Formula (I), (Ia), (Ib), (II) or (III) and those of theExamples. In some cases the compounds of Formula (I), (Ia), (Ib), (II)or (III) and the Examples can be more stable as salt forms as comparedto free base.

In reference to the synthetic schemes described herein the followingintermediates (and analogous intermediates or derivatives thereof) canbe made using the following procedures.

Intermediate A 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene

Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions toa solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL) After 10 mina solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35mmol) in DMSO (5 mL) was transferred via canula and the mixture wasstirred at room temperature for 6 h. The reaction was poured over water(10 mL) and extracted with Et₂O (3×10 mL); the organic layers werewashed with brine (2×15 mL), dried over anhydrous Na₂SO₄ and filtered.After removal of the solvent, the residual orange oil was purified bycolumn chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 gof 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20%EtOAc/hexanes), white solid, 26% yield].

Intermediate B Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine

Zn dust (1.97 g, 30 mol) was added in small portions, over a period of30 min, to a vigorously stirred solution of1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A,0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad ofcelite, that was washed with 10 mL of methanol. The filtrate wasconcentrated and 10 mL of water were added, washing with CH₂Cl₂ (3×15mL). The organic layers were dried over anhydrous Na₂SO₄ and filtered.After removal of the solvent, the crude product was purified by columnchromatography on silica gel (10% MeOH/CH₂Cl₂) affording 0.50 g of(trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10%MeOH/CH₂Cl₂), white solid, 70% yield]. ¹H-NMR (MeOH, 250 MHz, δ):7.45-7.27 (m, 5H, ArH); 6.96 (d, 8.5 Hz, 2H, ArH); 6.86 (d, J=8.5 Hz,2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 1H,CH); 0.98-0.85 (m, 2H, CH2).

Intermediate C (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate

Triethyl phosphonoacetate (26.6 g, 118.8 mmol) was added slowly dropwiseto a mixture of Potassium-tert-butoxide (14.5 g, 129.6 mmol) in dry THF(200 mL) at −5° C., stirred for 20 min and then a solution of6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL)was added slowly dropwise at −5° C. and stirred for 30 min. Aftercompletion, the reaction mixture was poured into ice water (350 mL) andextracted with EtOAc (2×300 mL). The combined organic extracts werewashed with saturated NaHCO₃ solution (250 mL), water (250 mL) and brine(250 mL) and dried over anhydrous Na₂SO₄, filtered and evaporated to get(E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (20 g, 72.9%) as brown colorliquid. This is carried to next step without further purification.

Intermediate D(Trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in smallportions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO(400 mL) at rt., stirred for 1 h until clear solution was obtained. Asolution of (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (Intermediate C,20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h.After completion, the reaction mixture was poured into ice water (700mL), extracted with EtOAc (2×350 mL). The combined organic extracts werewashed with water (250 mL), brine (250 mL) and dried over anhydrousNa₂SO₄, filtered and evaporated to give(trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10 g, 47%)as brown liquid.

Intermediate E (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylicacid hydrochloride

NaOH 4N solution (60 mL) was added to a solution of(trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate(Intermediate D, 10 g, 37.1 mmol) in methanol (100 mL) and the reactionmixture was stirred at RT for 4 h. After completion, the solvent wasevaporated and the residue was diluted with ice water (250 mL) andacidified with 4 N HCl solution, the aqueous layer was extracted withEtOAc (2×350 mL). The combined organic extracts were washed with water(250 mL), brine (250 mL) and dried over anhydrous Na₂SO₄, filtered andevaporated to give (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylicacid hydrochloride (5 g, 55.8%) as a light brown color solid.

Intermediate F (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide

Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of(trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride(Intermediate E, 5 g, 20.7 mmol) and Et₃N (14.2 mL, 103.7 mmol) inAcetone (100 mL) at −5° C., then reaction mixture was stirred at −5° C.for 1 h, then a solution of NaN₃ (2.7 g, 41.4 mmol) in water (10 mL) wasadded and stirred for 30 mins at RT. After completion the solvent wasevaporated under vacuum. The crude residue was dissolved in ethylacetate (200 mL), washed with water (80 mL), brine (80 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to get(trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5%)as a brown color gummy liquid.

Intermediate G tert-butyl(trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate

A solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide(Intermediate F, 2.5 g, 9.36 mmol) in tort-butanol (80 mL) was heated at90° C. for 16 h. After completion, the solvent was evaporated undervacuum and the residue was taken in water (100 mL) and extracted withEtOAc (2×100 mL). The combined organic extracts were washed with water(100 mL), brine (100 mL) and dried over anhydrous Na₂SO₄, filtered andevaporated. The crude residue was purified by flash columnchromatography (SiO₂) by eluting with EtOAc:Hexane (2:8) to gettert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (1.1 g,37.5%) as a light yellow solid. ¹H-NMR (CDCl₃) δ (ppm): 1.16 (q, 1H),1.23 (quin, 1H), 1.45 (s, 9H), 2.01 (m, 1H), 2.69 (m, 1H), 4.88 (br,1H), 7.36 (s, 2H), 8.20 (s, 1H).

Intermediate H (E)-ethyl 3-(4-bromophenyl)acrylate

A solution of triethyl phosphonoacetate (13.1 g, 0.0589 mol) was addedslowly (dropwise) to a solution of Potassium-tert-butoxide (6.59 g,0.0589 mol), in dry THF (150 mL) at −5° C., stirred for 30-45 mins atthe same temperature, then a solution of 4-Bromo benzaldehyde (10 g,0.054 mol), in dry THF (50 mL) was slowly added dropwise at −5° C. overa period of 15 mins, stirred the reaction mixture for 30 mins at thesame temperature. After completion of reaction by TLC, the reactionmixture was poured into ice water (300 mL), extracted with EtOAc (2×200mL). The combined organic extracts were washed with sat NaHCO₃ solution(200 mL), water (200 mL), brine (200 mL) and dried over anhydrousNa₂SO₄, filtered and evaporated to get crude (E)-ethyl 3-(4-bromophenyl)acrylate (10 g, 72%) as pale green liquid. This is carried to next stepwithout further purification.

Intermediate I (Trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly insmall portions over a period of 20 min. to a suspension of sodiumhydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h,till the formation of clear solution. Then a solution of (E)-ethyl3-(4-bromophenyl) acrylate (Intermediate H, 5 g, 0.01968), in dry DMSO(20 mL) was added slowly dropwise, stirred at rt for 30 mins. Aftercompletion of reaction, checked by TLC, the reaction mixture was pouredinto ice water (200 mL), extracted with EtOAc (2×150 mL). Combinedorganic extracts were washed with ice water (2×150 mL), brine (150 mL),dried over anhydrous Na₂SO₄, filtered and evaporated to get(trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as agreen liquid. The crude is carried to next step without furtherpurification.

Intermediate J (Trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid

NaOH 4N (20 mL) was added to a solution of (trans)-ethyl2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate I, 4 g, 0.0149mol), in Methanol (40 mL) and stirred at rt for 2 h. After completion ofreaction, checked by TLC, the solvent was evaporated and the residue wasdiluted with water (50 mL), acidified with HCl 4 N solution, the solidformed was filtered and dried to get(trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72%), as awhite solid.

Intermediate K (Trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide

Ethyl chloroformate (1.9 mL) was added to a solution of(trans)-2-(4-bromophenyl) cyclopropanecarboxylic acid (Intermediate J, 4g, 0.0165 mol) and Et₃N (2.51 mL, 0.0199 mol) in acetone (60 mL) at −20°C., stirred at same temperature for 1 h, then a solution of NaN₃ (1.3 g,0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt.After completion of reaction, checked by TLC, the solvent was evaporatedand crude residue was dissolved in ethyl acetate (100 mL), washed withwater (40 mL), dried over anhydrous Na₂SO₄, filtered and evaporated toget (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (4 g). The cruderesidue is carried to next step without further purification.

Intermediate L tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate

A solution of (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide(Intermediate K, 4 g) in tert-Butanol (40 mL) was heated at 90° C. for16 h. After completion of reaction, checked by TLC, the solvent wasevaporated residue was poured into water (50 mL), extracted with EtOAc(2×50 mL). The combined organic extracts were washed with water (50 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude residue was purified by column chromatography (SiO₂) by elutingwith EtOAc: Pethroleum ether (2:98), to get tert-butyl(trans)-2-(4-bromophenyl)cyclopropylcarbamate (2.5 g, 48% overall 2steps) as a white solid. ¹H-NMR (CDCl₃, 250 MHz) δ (ppm): 1.07-1.19 (m,2H), 1.44 (s, 9H); 2.05-1.94 (m, 1H); 2.72-2.62 (m, 1H); 4.85 (br, 1H);7.09-6.96 (m, 2H); 7.44-7.33 (m, 2H).

Intermediate M Ethyl5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate

Sodium hydride (280 mg, 0.007 mol) in DMF (10 mL) was added to asuspension of Ethyl 5-amino-1,3,4-oxadiazole-2-carboxylate (1 g, 0.006mol) in DMF (2 mL) at 0° C., stirred for 10 mins, then Di tert-butyldicarbonate (1.65 g, 0.0076 mol) was added and stirred at RT for 16 h.After completion, the reaction mixture was poured into ice water (25 mL)and extracted with EtOAc (3×25 mL) The combined extracts were washedwith cold water (2×25 mL), brine (25 mL), dried over anhydrous Na₂SO₄,filtered and evaporated. The crude residue was purified by columnchromatography (SiO₂) using EtOAc: Petroleum ether (1:3) as eluent toget Ethyl 5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate(900 mg, 56.2%) as a white solid.

Intermediate N Tert-butyl(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)carbamate

NaBH₄ (330 mg, 0.0087 mol) was added to a solution of Ethyl5-((tert-butoxycarbonyl)amino)-1,3,4-oxadiazole-2-carboxylate(Intermediate M, 900 mg, 0.0035 mol) in THF (18 mL) at 0° C. and stirredat RT for 16 h. After completion, the solvent was evaporated and theresidue was taken in water (15 mL) and extracted with EtOAc (3×20 mL).The combined extracts were washed with water (20 mL), brine (20 mL),dried over anhydrous Na₂SO₄, filtered and evaporated. The crude residuewas purified by column chromatography (SiO₂) using EtOAc: Petroleumether (8:2) as eluent to get tert-butyl(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl) carbamate (450 mg, 54.2%) as awhite solid.

Intermediate O Tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate

MnO₂ (500 mg) was added to a solution of tert-butyl(5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl) carbamate (Intermediate N, 450mg, 0.0021 mol) in THF (9 mL) at RT and stirred for 16 h. Aftercompletion, the reaction mixture was filtered through a pad of celiteand the filtrate was evaporated to get crude tert-butyl(5-formyl-1,3,4-oxadiazol-2-yl)carbamate (250 mg). This crude wascarried to next step without further purification.

Intermediate P 4-(benzyloxy)benzaldehyde

Potassium Carbonate (678 g, 4.91 mol) was added to a solution of4-hydroxybenzaldehyde (200 g, 1.63 mol) in DMF (2 L) followed to theaddition of benzyl bromide (214 mL, 1.80 mol) at 0° C. and stirred for18 h at RT. After completion, the reaction mixture was poured into icewater (3 L), filtered the solid and dried to get4-(benzyloxy)benzaldehyde (230 g, 66%).

Intermediate Q (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate

Triethyl phosphonoacetate (259 mL, 1.3 mol) was added slowly drop wiseto a solution of Potassium-tert-butoxide (145 g, 1.29 mol) in dry THF (2L) at −5° C. and stirred for 30-45 mins. Then a solution of4-(benzyloxy)benzaldehyde (Intermediate P, 230 g, 1.08 mol) in dry THF(1.5 L) was added slowly drop wise at −10° C. over a period of 15 minsand stirred for 30 mins. After completion, the reaction mixture waspoured into ice water (1 L) and extracted with EtOAc (2×1.5 L). Thecombined organic extracts were washed with sat NaHCO₃ solution (1 L),water (1 L), brine (1 L), dried over anhydrous Na₂SO₄, filtered andevaporated to get crude (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (290g, 95%). The crude was carried to next step without furtherpurification.

Intermediate R (Trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (224 g, 1.02 mol) was added portion wise toa suspension of NaH (40.8 g, 1.02 mol) in dry DMSO (2 L) at RT over aperiod of 20 min and stirred for 1 h till the formation of a clearsolution. A solution of (E)-ethyl 3-(4-(benzyloxy) phenyl) acrylate(Intermediate Q, 240 g, 0.85 mol) in dry DMSO (2 L) was added drop wiseand stirred at RT for 30 mins. After completion, the reaction mixturewas poured into ice water (2 L), extracted with EtOAc (2×1 L). Combinedorganic extracts were washed with ice water (1 L), brine (1 L), driedover anhydrous Na₂SO₄, filtered and evaporated to afford (Trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (142 g, 58.6%) as an offwhite solid. The crude was carried to next step without furtherpurification.

Intermediate S (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylicacid

4N NaOH solution (4 L) was added to a solution of (trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (Intermediate R, 250 g,0.844 mol) in Methanol (1.2 L) at 0° C. and stirred at RT for 4 h. Aftercompletion, the solvent was evaporated, the residue was diluted withwater (1 L), acidified with 4 N HCl solution, extracted with EtOAc (2×2L). Combined organic extracts were washed with water (1 L), brine (1 L),dried over anhydrous Na₂SO₄, filtered and evaporated to afford(trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylic acid (190 g, 84%)as off white solid. The crude was carried to next step without furtherpurification.

Intermediate T (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide

Ethyl chloroformate (143 mL, 1.48 mol) was added to a solution of(trans)-2-(4-(benzyloxy) phenyl)cyclopropanecarboxylic acid(Intermediate S, 190 g, 0.70 mol), Triethyl amine (229 mL, 1.63 mol) inacetone (2.8 L) at −20° C. and stirred for 1 h, then a solution of NaN₃(138 g, 2.1 mol) in water (200 mL) was added and stirred at RT for 30mins. After completion, the solvent was evaporated, residue wasdissolved in EtOAc (2 L), washed with water (2 L), brine (1 L), driedover anhydrous Na₂SO₄, filtered and evaporated to afford(trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide (178 g,85.9%).

Intermediate U Tert-butyl((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate

A solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide(Intermediate T, 178 g, 0.64 mol) in tert-butanol (2.6 L) was heated at90° C. for 16 h. After completion, the solvent was evaporated and thecrude residue was purified by column chromatography by using (SiO₂)EtOAc: Pet ether (4:96) to get tert-butyl((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate (78 g, 37.8%) asoff-white solid.

Intermediate V (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanaminehydrochloride

HCl in Dioxane (390 ml) was added to a solution of tert-butyl((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate (Intermediate U,78 g, 0.23 mol) in 1,4-dioxane (780 mL) at 0° C. and stirred at RT for12 h. After completion, the solvent was evaporated and the residue wastriturated with diethyl ether (1 L) followed by hexane (1 L) to give(trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine hydrochloride (55 g,87%) as off-white solid.

Intermediate W ethyl 2-amino-2-thioxoacetate

P₂S₅ (28.5 g, 128 mmol) was added portion wise to a solution of ethyl2-amino-2-oxoacetate (30 g, 25.6 mmol) in pyridine (300 mL) over aperiod of 30 mins, and stirred at 90° C. for 3 h. After completion, thesolvent was evaporated, the residue was diluted with water (300 mL) andextracted with EtOAc (2×300 mL). The combined extracts were washed withwater (2×200 mL), brine (200 mL) and dried over anhydrous Na₂SO₄,filtered and evaporated. The crude was purified by column chromatography(SiO₂) by eluting (1:9) EtOAc:Hexane to afford ethyl2-amino-2-thioxoacetate (18 g, 52.9%) as white solid.

Intermediate X 2-(ethoxycarbonyl)thiazole-5-carboxylic acid

Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl2-amino-2-thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane(200 mL) and refluxed for 5 h. After completion the reaction mixture waspoured into water (200 mL), the residue was basified with sat NaHCO₃ andextracted with EtOAc (2×250 mL). The aqueous layer was acidified with 2NHCl and extracted with EtOAc (2×250 mL) The combined extracts werewashed with water (250 mL), brine (250 mL), dried over anhydrous Na₂SO₄,filtered and evaporated to afford2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude wascarried to next step without further purification.

Intermediate Y Ethyl 5-(azidocarbonyl)thiazole-2-carboxylate

Ethyl chloroformate (9.8 g, 83.6 mmol) was added to a solution of2-(ethoxycarbonyl)thiazole-5-carboxylic acid (Intermediate X, 13 g,64.67 mmol), TEA (9.79 g, 97.01 mmol) in acetone (130 mL) at −20° C.,stirred for 1 h, then a solution of NaN₃ (5.4 g, 83.6 mmol) in water (15mL) was added and stirred at RT for 30 mins. After completion, thesolvent was evaporated, the crude residue was diluted with water (150mL) and extracted with EtOAc (2×150 mL). The combined extracts werewashed with water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄,filtered and evaporated to afford Ethyl5-(azidocarbonyl)thiazole-2-carboxylate (11 g crude) as brown liquid.The crude was carried to next step without further purification.

Intermediate Z Ethyl5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate

A solution of ethyl 5-(azidocarbonyl)thiazole-2-carboxylate(Intermediate Y, 11 g, 48.6 mmol) in tert-butanol (150 mL) was refluxedat 90° C. for 16 h. After completion, the solvent was evaporated. Thecrude residue was purified by column chromatography by using (SiO₂),eluting with EtOAc: Petroleum ether (2:98) to afford Ethyl5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylate (4 g, 30.23%) aswhite solid.

Intermediate AA Tert-butyl (2-(hydroxymethyl)thiazol-5-yl)carbamate

NaBH₄ (1.1 g, 29.2 mmol) was added portion wise to a solution of Ethyl5-(tert-butoxycarbonyl amino)thiazole-2-carboxylate (Intermediate Z, 4g, 14.6 mmol) in MeOH (40 mL) at 0° C. over a period of 30 mins andstirred at RT for 16 h. After completion, solvent was evaporated, thesolid residue was dissolved in ice water (50 mL) and extracted withEtOAc (2×50 mL) The combined extracts were washed with water (50 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude was purified by column chromatography by using SiO₂, eluting withEtOAc:Petroleum ether (2:8) to afford Tert-butyl(2-(hydroxymethyl)thiazol-5-yl)carbamate (2.9 g, 84.8%) as white solid.

Intermediate AB Tert-butyl (2-formylthiazol-5-yl)carbamate

MnO₂ (1.5 g, 18.2 mmol) was added to a solution of Tert-butyl(2-(hydroxymethyl)thiazol-5-yl)carbamate (Intermediate AA, 700 mg, 3.04mmol) in DCM (15 mL) and stirred at RT for 16 h. After completionreaction mixture was diluted with DCM, filtered through celite. Thefiltrate was concentrated under vacuum to afford Tert-butyl(2-formylthiazol-5-yl)carbamate (500 mg crude). The crude was carried tonext step without further purification.

The compounds described in examples 1-24 are racemic, that is to say a50:50 mixture of the enantiomers corresponding the trans racemate.

Example 15-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine

Sodium triacetoxy borohydride (883 mg, 4.166 mmol) was added slowly at0° C. to a solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine(Intermediate B, 500 mg, 2.083 mmol), 2-aminopyrimidine-5-carbaldehyde(256 mg, 2.083 mmol) in DCE (10 mL) and stirred for 20 h. Aftercompletion, the solvent was evaporated. The residue was dissolved inMethanol (15 mL), NaBH₄ (237 mg, 6.249 mmol) was added slowly at 0° C.and stirred for 3 h. After completion, the solvent was evaporated, theresidue was dissolved in ice water (20 mL) and extracted with EtOAc(2×20 mL) The combined organic layers were washed with brine (20 mL) anddried over anhydrous Na₂SO₄, filtered and evaporated. The crude residuewas purified by prep HPLC to afford5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)pyrimidin-2-amine(180 mg, 25%) as white solid. ¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.85(q, 1H), 0.90 (quin, 1H), 1.73 (m, 1H), 2.07 (m, 1H), 2.75 (brs, 1H),3.53 (s, 2H), 5.04 (s, 2H), 6.46 (s, 2H), 6.85 (d, 2H), 6.92 (d, 2H),7.33 (m, 1H), 7.42 (m, 4H), 8.11 (s, 2H). Mass (M+H): 347.3

Following example has been synthesized using the procedure described forExample 1 and the corresponding starting materials.

Example 25-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-aminehydrochloride

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.22 (q, 1H), 1.48 (quin, 1H), 2.46(m, 1H), 2.80 (br, 1H), 4.35 (s, 2H), 5.08 (s, 2H), 6.93 (d, 2H), 7.06(d, 2H), 7.32 (m, 2H), 7.40 (m, 4H), 8.98 (br, 1H), 9.90 (br, 2H). Mass(M+H): 351.9

The following compounds can be synthesized following the methodologydescribed in Scheme 1 and 2 or other synthetic routes known to theordinary skilled artisan.

Example 35-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)pyrimidin-2-amine

Example 45-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylamino)methyl)thiazol-2-amine

Example 53-(5-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol

Example 63-(5-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)pyridin-2-yl)phenol

Example 74′-((trans)-2-((2-aminopyrimidin-5-yl)methylamino)cyclopropyl)biphenyl-3-ol

Example 84′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol

Example 95-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine

Example 105-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine

This compound can be synthesized following scheme 1 or scheme 3, orother synthetic routes known to the ordinary skilled artisan.

Scheme 1 Procedure

Step 1:

Tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate (Intermediate O, 220mg, 1.041 mmol) and sodium triacetoxy borohyride (441 mg, 2.08 mmol) wasadded to a solution of Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine(Intermediate B, 250 mg, 1.041 mmol) in dry Dichloro ethane (2.5 mL) at0° C. and stirred at RT for 24 h, then the solvent was evaporated. Theresidue was taken in MeOH (2.5 mL) and NaBH₄ (116 mg, 3.138 mmol) wasadded at 0° C. and stirred for 2 h at RT. After completion, the solventwas evaporated, the residue was taken in water (10 mL) and extractedwith EtOAc (4×10 mL) Combined extracts were washed with water (10 mL),brine (10 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. Theresidue was purified by column chromatography (SiO₂) using MeOH:CHCl₃(1:99) to get tert-butyl(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate(70 mg, 15.3%) as pale green liquid.

Step 2:

HCl in 1, 4 dioxane (1 mL) was added to a solution of tert-butyl(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate(100 mg) in 1, 4 dioxane (1 mL) at 0° C. and stirred for 18 h. Aftercompletion, the solvent was evaporated and residue was dissolved inwater (10 mL), basified with Na₂CO₃ solution, extracted with EtOAc (3×5mL) The combined extracts were washed with water (5 mL), brine (5 mL),dried over anhydrous Na₂SO₄, filtered and evaporated. The crude residuewas purified by column chromatography using MeOH: CHCl₃ (5:95) as eluentto afford5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine(40 mg, 52%) as a white solid.

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.85 (m, 2H), 1.72 (m, 1H), 2.2 (m,1H), 3.0 (m, 1H), 3.75 (s, 2H), 5.08 (s, 2H), 6.8-7.0 (m, 6H), 7.4 (m,5H); Mass (M+H): 337.1

Scheme 3 Procedure

This compound can be synthesized following the same method as describedin the Scheme 1 procedure but, in Step 1, the intermediate V is usedinstead of intermediate B.

The following compounds can be synthesized following the methoddescribed for example 10 using Scheme 3 procedure and the correspondingcommercial available alkyl halides to get the suitable Intermediate Pderivatives.

Example 115-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

¹HNMR (400 MHz, DMSO d6) δ (ppm): 0.84 (m, 2H), 1.79 (m, 1H), 2.20 (m,1H), 3.12 (m, 1H), 3.78 (s, 1H), 5.02 (s, 2H), 6.85-7.00 (m, 6H), 7.2(t, 2H), 7.46 (t, 2H); Mass (M−H): 353.3

Example 125-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

¹HNMR (400 MHz, DMSO d6) δ (ppm): 0.85 (m, 2H), 1.73 (m, 1H), 2.19 (m,1H), 3.00 (m, 1H), 3.75 (s, 2H), 5.07 (s, 2H), 6.85-7.00 (m, 6H), 7.14(t, 1H), 7.25 (t, 2H), 7.41 (m, 1H); Mass (M−H): 353.3

Example 135-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

¹HNMR (400 MHz, DMSO d6) δ (ppm): 0.87 (m, 2H), 1.75 (m, 1H), 2.20 (m,1H), 3.04 (m, 1H), 3.75 (s, 2H), 5.13 (s, 2H), 6.80-7.05 (m, 6H), 7.16(m, 3H); Mass (M+H): 373.0

Example 145-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

¹HNMR (400 MHz, DMSO d6) δ (ppm): 0.86 (m, 2H), 1.73 (m, 1H), 2.18 (m,1H), 2.98 (m, 1H), 3.75 (s, 2H), 5.05 (s, 2H), 6.82-6.95 (m, 6H), 7.44(m, 4H); Mass (M−H): 369.0

Example 155-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

¹HNMR (400 MHz, DMSO d6) δ (ppm): 0.85 (m, 2H), 1.73 (m, 1H), 2.19 (m,1H), 3.00 (m, 1H), 3.75 (s, 2H), 5.07 (s, 2H), 6.84-7.02 (m, 6H),7.39-7.54 (m, 4H); Mass (M+H): 371.0

The following compounds can be synthesized following the methodologhydescribed in Scheme 1, 2 and 3. Alternatively, as known by those skilledin the art, the following compounds can also be obtained from the(trans)-cyclopropanamine derivatives of formula (3) and (24),respectively, by a well-known reactions (i.e., heterocycle formation orcyclization)

Example 165-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

Example 175-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine

Example 18N-(5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide

Example 194′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol

Example 205-((((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

Example 215-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine

Example 222-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine

Example 234-((((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine

Example 242-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine

Example 253-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine

Example 265-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1,3,4-oxadiazol-2-amine

Example 273-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine

Example 285-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine

Example 295-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridin-2-amine

Example 306-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyridazin-3-amine

Example 315-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrazin-2-amine

Example 322-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-5-amine

Example 336-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-3-amine

Example 343-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-triazin-6-amine

Example 35 Preparation of Enantiomerically Enriched or Optically ActiveCompounds

5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-aminecan be synthesized according to the procedure describe in example 10.Alternatively, enantiomerically enriched or pure intermediates can beprepared and then used in subsequent reactions in order to synthesizethe corresponding (−) or (+) enantiomer, e.g., of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine.

Step 1

R-(−)-Mandelic acid (22.2 g, 0.14 mol) was added to a solution of(trans)-2-(4-(benzyloxy)phenyl)cyclopropanamine hydrochloride(intermediate V) (35 g, 0.14 mol) in a mixture of THF and H₂O (6:4) (650mL) and refluxed for 1 h. After formation of a clear solution thereaction mixture was cooled to RT. The solid precipitated formed wasfiltered, basified with sat. NaHCO₃ solution and extracted with ethylacetate (3×500 mL). The combined organic extracts were washed with water(500 mL), brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to afford trans2-(4-(benzyloxy)phenyl)cyclopropanamine (enantiomer-(−)) (14 g, 46.6%)as an off white solid.

Step 2

Tert-butyl (5-(chloromethyl)-1,3,4-oxadiazol-2-yl)carbamate (141 mg,0.606 mmol) was added to a solution of2-(4-(benzyloxy)phenyl)cyclopropanamine (enantiomer (−)) (145 mg, 0.606mmol) and K₂CO₃ (166 mg, 1.213 mmol) in dry DMF (1.5 mL) and stirred atRT for 2 h. After completion, the reaction mixture was poured into icewater (10 mL) and extracted with EtOAc (4×10 mL). The combined organicextracts were washed with water (3×10 mL), brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residueobtained was purified by column chromatography (SiO₂) using MeOH:CHCl₃(1:99) as eluent to afford tert-butyl(5-(((2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate(enantiomer-(−)) (100 mg, 37.7%) as a pale green liquid.

Step 3

To a solution of (−) tert-butyl5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-ylcarbamate (100 mg, 0.229 mmol) in 1, 4 dioxane (1 mL) at 0° C. was addedHCl in 1, 4 dioxane (1 mL) and stirred for 18 h. After completion, thesolvent was evaporated and residue was dissolved in water (10 mL),basified with Na2CO3 solution, extracted with EtOAc (3×5 mL). Thecombined extracts were washed with water (5 mL), brine (5 mL), driedover anhydrous Na2SO4, filtered and evaporated. The crude residue waspurified by column chromatography using MeOH: CHCl3 (5:95) as the eluentto afford (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine(40 mg, 52%) as a white solid.

¹HNMR (400 MHz, DMSO d6) δ: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H), 5.0(s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H),0.92 (m, 2H)

Mass (M+H): 337.1

HPLC Purity: 96.02%

Chiral HPLC Purity: 95.12%

Specific optical rotation [α]_(D) ^(27.2) (c=0.5% in DMSO): −37.76°

The corresponding enantiomer-(+) can be synthesized by following thesame procedure but using S-(+)-Mandelic acid in Step 1.

¹H-NMR (400 MHz, DMSO d6) δ: 7.46 (t, 2H), 7.2 (t, 2H), 6.98 (q, 6H),5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2 (brs, 1H), 1.79 (brs, 1H),0.92 (m, 2H);

Mass (M+H): 337.1

HPLC Purity: 98.16%

Chiral HPLC Purity: 98.34%

Specific optical rotation [α]_(D) ^(26.9) (C=0.5% in DMSO): +37.76°

Salts for chiral recrystallization include S (+) Mandelic acid,

D (−) tartaric acid,

L (−) di-p-toluoyl tartaric acid, or

R (−) Mandelic acid.

The following compounds can be prepared according to the syntheticdescription provided herein and the skill of an ordinary skilledartisan, wherein the absolute configuration is as specified in the drawnstructure:

-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine

-   N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide

-   N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)pyrimidin-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)    pyrimidin-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1,3,4-oxadiazol-2-amine

-   5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N,N-dimethyl-1,3,4-oxadiazol-2-amine

Example 36 Isolation of Single Enantiomers of (Trans) RacemicN-Substituted Aryl- or Heteroaryl-Cyclopropylamine Compounds

Chiral HPLC: Conditions to perform the chiral separation of compounds orintermediates of the invention can be similar to the following:

Separation by chiral preparative HPLC: Every injection is prepared frome.g., about 15 mg of the N-substituted aryl- orheteroaryl-trans-cyclopropylamine compound dissolved in a mixture ofEtOH, n-pentane and HFIPA (1,1,1,3,3,3-Hexafluoro-2-propanol). Theoptically active N-substituted aryl- orheteroaryl-trans-cyclopropylamine compound (e.g., (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine)can be separated on e.g., a ChiralPak-IA (250×20 mm ID) 5 μM at ambienttemperature eluting with 0.1% DEA in 70/30 hexane/EtOH at 18 mL/min. Thesolutions from the chiral separation can be concentrated under vacuum(15 psi, 35° C.) to afford the resolved enantiomers.

Analytical determination of enantiomeric excess (ee): ChiralPak IA250×4.6 mm ID, 5 μm, 0.1% DEA in 80/20 hexane/EtOH at 1 mL/min atambient temperature, with UV analysis at 230 nm Enantiomers eluted at11.35 and 16.51 min, each with >90% enantiomeric excess.

Analytical purity: Acquity UPLC BEH C18 100×2.1 mm ID, 1.7 μm, 0.025%TFA in a gradient H2O:ACN (T/% B, 0/30, 4/80, 6/80, 6.1/30) at 0.4mL/min at ambient temperature, with UV analysis at 229 nm. Elution at1.64 min, each with >95.0% purity. Without being bound by theory, it isbelieved that mixtures, e.g., racemates corresponding to a compound ofFormula (I), (Ia), (Ib), (II) or (III) can be resolved in the individualenantiomers or an enantiomer substantially free of the other enantiomer.Thus, the skilled artisan, in view of the disclosure described hereincan isolate or purify enantiomers from racemates or mixtures ofenantiomers in view of the disclosure herein utilizing standard organicchemistry techniques for separating enantiomers.

Enantiomer 1, the (−) optical stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineis characterized as follows: ¹HNMR (400 MHz, DMSO d6) δ: 7.46 (t, 2H),7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2(brs, 1H), 1.79 (brs, 1H), 0.92 (m, 2H); Mass (M+H): 337.1; HPLC Purity:96.02%; Chiral HPLC Purity: 95.18%; Specific optical rotation [α]_(D)^(27.2) (c=0.5% in DMSO): −37.76°.

Enantiomer 2, the (+) optical stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineis characterized as follows: ¹HNMR (400 MHz, DMSO d6) δ: 7.46 (t, 2H),7.2 (t, 2H), 6.98 (q, 6H), 5.0 (s, 2H), 3.78 (s, 1H), 3.1 (brs, 1H), 2.2(brs, 1H), 1.79 (brs, 1H), 0.92 (m, 2H); Mass (M+H): 337.1; HPLC Purity:98.16%; Chiral HPLC Purity: 98.34%; Specific optical rotation [α]_(D)^(26.9) (c=0.5% in DMSO): +37.76°.

The optical activity determination experiment was performed with aJasco-P-1030 Polarimeter at a temperature of about 26.9 and 27.2 and acompound concentration (0.5%) and solvent of choice e.g., (DMSO).

Example 37 Determination of Kinetic Parameters for Optically ActiveCompounds of the Invention

The kinetic parameters of LSD1 demethylase inhibition were obtainedusing the peroxidase-coupled reaction method. In this assay thedemethylase reaction was initiated by simultaneously mixing LSD1 protein(either 31 nM or 10 nM) (BPS), 31.25 μM H3-K4me2 peptide (Millipore),increasing concentrations of test compound (e.g., an optically activestereoisomer of5-(((Trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineor an optically active N-substituted aryl- orheteroaryl-cyclopropylamine compound) and 501.1M Amplex® Red and 0.1U/ml horseradish peroxidase (HPR) (Invitrogen) in a buffer containing 50mM sodium phosphate buffer pH=7.4. The final DMSO concentration was 0.7%and constant in all assay wells.

The conversion of the Amplex® Red reagent to resorufin due to generationof H₂O₂ was continuously monitored by fluorescence (excitation at 540nm, emission at 590 nm) using a microplate reader (Infinite 200, Tecan).A solution of 1 μM H₂O₂ was used to calibrate the fluorescence signaland the temperature was kept constant at 25° C.

Kinetic parameters were obtained following the method described bySzewczuk et al ((2007) Biochemistry, 46, 6892-6902).

Briefly, progress curves obtained in the presence of test compound werefit to derive kobs (k) based on the following equation:

${product} = {\frac{v_{0}\left( {1 - {\mathbb{e}}^{- {kt}}} \right)}{k} + {offset}}$

The kobs values were then used to derive the kinetic constant by usingthe following equations (Kitz and Wilson analysis):

k = (k_(inact)[I])/(K_(I(app)) + [I])$K_{I} = \frac{K_{I{({app})}}}{1 + \frac{\lbrack S\rbrack}{Km}}$with  Km = 24  μM.

The determination of the kinetic inhibition constants for MAOs was donefollowing the same protocol as for LSD1 with the followingmodifications:

For MAO-A, the protein was kept at 1.8 ng/ul (Sigma M7316) andkynuramine (Sigma) at 64 uM was used as substrate. In this case the Kmwas 64 uM.

For MAO-B, the protein was kept between 1.8 and 3.6 ng/ul (Sigma M7441)and kynuramine (Sigma) at 50 uM was used as substrate. In this case theKm was 32 uM.

For both MAO assays, the final DMSO concentrations were 0.54%.

Selegine hydrochloride and rasagiline mesylate were obtained fromSigma-Aldrich and Carbone Scientific Co. Ltd respectively.

These studies were used to calculate the values obtained in Table 1.

TABLE 1 The Catalytic Efficiency, k_(inact)/K_(I), Obtained for theEnantiomers of 5-(((Trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine k_(inact)IK_(I) (M⁻¹s⁻¹) Enantiomer −1 Enantiomer −2 (−) optical (+) optical antipodeantipode Selegiline Rasagiline LSD1 15,516   767 Inactive Inactive MAO-A   17   182 <100   62 MAO-B 38,298 34,940 32,500 7,463

The results described herein show that the (−) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amineis a potent, highly selective inhibitor of LSD1 and MAOB. Theselectivity of the (−) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-aminefor LSD1, MAO-A, and MAO-B as judged by the selectivity indexk_(inact)/K_(I) indicates that the compound is highly selective for bothLSD1 and MAO-B. In particular, the selectivity index of the (−)stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-aminefor MAO-B/MAO-A is about 2253 and is thus more advantageous than thecorresponding values for Rasagiline and Selegiline which are 120 and<325, respectively. The selectivity index of the (+) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-aminefor MAO-B/MAO-A is about 192. Furthermore, other irreversible monoamineoxidase inhibitors like Rasagiline and Selegiline are not active againstLSD1 in these assays. Notably, the ratio of k_(inact)/K_(I) forLSD1/MAO-A was over 100-larger for the (−) stereoisomer as compared tothe (+) stereoisomer of5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine.Thus, the inventors have unexpectedly found that optically activeN-substituted aryl- or heteroaryl-trans-cyclopropylamine compounds,including the compounds of Formula (I), wherein the substituents on thecyclopropyl moiety are in trans orientation, as well as the compounds ofFormula (II) or (III), have unexpected selectivity for inhibiting LSD1and for inhibiting LSD1 and MAO-B.

Example 38 Biological Assays

The compounds of the invention can be tested for their ability toinhibit LSD1. The ability of the compounds of the invention to inhibitLSD1 can be tested as follows. Human recombinant LSD1 protein waspurchased from BPS Bioscience Inc. In order to monitor LSD1 enzymaticactivity and/or its inhibition rate by our inhibitor(s) of interest,di-methylated H3-K4 peptide (Millipore) was chosen as a substrate. Thedemethylase activity was estimated, under aerobic conditions, bymeasuring the release of H₂O₂ produced during the catalytic process,using the Amplex® Red peroxide/peroxidase-coupled assay kit (Invitrogen,Carlsbad, Calif.).

Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, inthe absence and/or in the presence of various concentrations ofinhibitor (e.g., from 0 to 75 μM, depending on the inhibitor strength).Tranylcypromine (Biomol International) was used as a control forinhibition. Within the experiment, each concentration of inhibitor wastested in duplicate. After leaving the enzyme interacting with theinhibitor, 12.5 μM of di-methylated H3-K4 peptide was added to eachreaction and the experiment was left for 30 minutes (or e.g., an hour)at 37° C. in the dark. The enzymatic reactions were set up in a 50 mMsodium phosphate, pH 7.4 buffer. At the end of the incubation, Amplex®Red reagent and horseradish peroxidase (HPR) solution were added to thereaction according to the recommendations provided by the supplier(Invitrogen), and mixed well for 5 minutes (e.g., or alternatively 30minutes) at room temperature in the dark. A 1 μM H₂O₂ solution was usedas a control of the kit efficiency. The conversion of the Amplex® Redreagent to resorufin due to the presence of H₂O₂ in the assay, wasmonitored by fluorescence (excitation at 540 nm, emission at 590 nm)using a microplate reader (Infinite 200, Tecan). Arbitrary units wereused to measure level of H₂O₂ produced in the absence and/or in thepresence of inhibitor.

The maximum demethylase activity of LSD1 was obtained in the absence ofinhibitor and corrected for background fluorescence in the absence ofLSD1. The Ki (IC50) of each inhibitor was estimated at half of themaximum activity.

The results presented in Table 2 below show the results of the LSD1inhibition studies for a number of the Example compounds. Parnate(2-trans phenylcyclopropylamine) was found to have a Ki (IC50) of fromabout 15 to 35 micromolar depending on the enzyme preparation. Thestudies show that the compounds of the invention have unexpectedlypotent LSD1 inhibition.

Example 39 Biological Assays—Monoamine Oxidase Assays for Determiningthe Selectivity of the Compounds of the Invention for LSD1

Human recombinant monoamine oxidase proteins MAO-A and MAO-B werepurchased from Sigma Aldrich. MAOs catalyze the oxidative deamination ofprimary, secondary and tertiary amines. In order to monitor MAOenzymatic activities and/or their inhibition rate by inhibitor(s) ofinterest, a fluorescent-based (inhibitor)-screening assay was set up.3-(2-Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, SigmaAldrich), a non fluorescent compound was chosen as a substrate.Kynuramine is a non-specific substrate for both MAOs activities. Whileundergoing oxidative deamination by MAO activities, kynuramine isconverted into 4-hydroxyquinoline (4-HQ), a resulting fluorescentproduct.

The monoamine oxidase activity was estimated by measuring the conversionof kynuramine into 4-hydroxyquinoline. Assays were conducted in 96-wellblack plates with clear bottom (Corning) in a final volume of 100 μL.The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performedin triplicate within the same experiment.

Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg for MAO-B)was incubated on ice for 15 minutes in the reaction buffer, in theabsence and/or in the presence of various concentrations of inhibitor(e.g., from 0 to 50 μM, depending on the inhibitor strength).Tranylcypromine (Biomol International) was used as a control forinhibition.

After leaving the enzyme(s) interacting with the inhibitor, 60 to 90 μMof kynuramine was added to each reaction for MAO-B and MAO-A assayrespectively, and the reaction was left for 1 hour at 37° C. in thedark. The oxidative deamination of the substrate was stopped by adding50 μL (v/v) of NaOH 2N. The conversion of kynuramine to4-hydroxyquinoline, was monitored by fluorescence (excitation at 320 nm,emission at 360 nm) using a microplate reader (Infinite 200, Tecan).Arbitrary units were used to measure levels of fluorescence produced inthe absence and/or in the presence of inhibitor.

The maximum of oxidative deamination activity was obtained by measuringthe amount of 4-hydroxyquinoline formed from kynuramine deamination inthe absence of inhibitor and corrected for background fluorescence inthe absence of MAO enzymes. The Ki (IC50) of each inhibitor wasdetermined at Vmax/2.

TABLE 2 Summary of Data from MAO-A, MAO-B, and LSD1 Inhibition StudiesExample MAO-A MAO-B LSD1 No. (Ki) (Ki) (Ki) 1 I II III 2 I I III 10 I IIII-III 11 I II II 12 I II II 13 I II II 14 I II II 15 I II II-III Theranges for the Ki value reported in Table 2 are for MAO-A, MAO-B andLSD1- I = between 1 μM and 40 μM; II = between 0.1 μM and 1 μM; IIIbetween 0.001 μM and 0.1 μM.

Generally the compounds of the Examples were found to have Ki (IC50)values for MAO-A and MAO-B greater than the LSD1 Ki values, whereas LSD1Ki values were lower than 0.6 μM.

Thus the compounds of the invention are unexpectedly potent LSD1inhibitors and unexpectedly selective for LSD1 as compared to MAO-A andMAO-B, or the compounds are dual inhibitors of LSD1 and MAO-B.

Some compounds of the Examples have been tested forantiproliferative/cytotoxic activity and been found to have activity inthe micromolar to low micromolar range against cancer cell linesincluding HCT-116.

Previous reports of LSD1 have found that it is involved in cellproliferation and growth. Some studies have implicated LSD1 as atherapeutic target for cancer. Huang et al. (2007) PNAS 104:8023-8028found that polyamine inhibitors of LSD1 modestly cause the reexpressionof genes aberrantly silenced in cancer cells and particularly colorectalcancer (Huang et al. Clin Cancer Res. (2009) Dec. 1; 15(23):7217-28.Epub 2009 Nov. 24. PMID: 19934284). Scoumanne et al. ((2007) J. Biol.Chem. May 25; 282(21):15471-5) found that deficiency in LSD1 leads to apartial cell cycle arrest in G2/M and sensitizes cells to growthsuppression induced by DNA damage. Kahl et al. ((2006) Cancer Res.66(23):11341-7.) found that LSD1 expression is correlated with prostatecancer aggressiveness. Metzger et al. reported that LSD1 modulation bysiRNA and pargyline regulates androgen receptor (AR) and may havetherapeutic potential in cancers where AR plays a role, like prostate,testis, and brain cancers. Lee et al. ((2006) Chem. Biol. 13:563-567)reported that tranylcypromine derepresses Egr-1 gene expression in somecancer lines. A body of evidence is accumulating that Egr-1 is a tumorsuppressor gene in many contexts (see e.g., Calogero et al. (2004)Cancer Cell International 4:1 exogenous expression of EGR-1 resulted ingrowth arrest and eventual cell death in primary cancer cell lines;Lucerna et al. (2006) Cancer Research 66, 6708-6713 show that sustainedexpression of Egr-1 causes antiangiogeneic effects and inhibits tumorgrowth in some models; Ferraro et al. ((2005) J. Clin. Oncol. March 20;23(9):1921-6) reported that Egr-1 is downregulated in lung cancerpatients with a higher risk of recurrence and may be more resistant totherapy. Thus, increasing Egr-1 expression via inhibition of LSD1 is atherapeutic approach for some cancers. Recent studies have alsoimplicated LSD1 in brain cancer (Schulte et al. (2009) Cancer Res. March1; 69(5):2065-71). Other studies have implicated LSD1 in breast cancer(Lims et al. Carcinogenesis. 2009 Dec. 30. [Epub ahead of print] PMID:20042638).

Thus, a body of evidence has implicated LSD1 in a number of cancers,which suggests that LSD1 is a therapeutic target for cancer. The instantinventors have discovered a class of LSD1 inhibitors that can be used totreat diseases where LSD1 is implicated as a therapeutic target likecancer. Accordingly, the phenylcyclopropylamine compounds of theinvention can be used to treat such diseases.

Recent studies have also implicated LSD1 in viral infection andreactivation. In particular it was shown that pharmacological inhibitorsof LSD1 like parnate and siRNA knock down of LSD1 caused reduced viralinfectivity and reduced reactivation after latency (Liang et al. (2009)Nat. Med. 15:1312-1317). Therefore it is believed that the compounds ofthe invention can be used for treating or preventing viral infection.Furthermore, it is believed that the compounds of the invention cantreat or prevent viral reactivation after latency.

Thus, without being bound by theory, the inventors have identified a newclass of cyclopropanamine derivatives containing LSD1 inhibitors withunexpected potency and selectivity for LSD1 a biologically relevanttarget in oncology and other diseases and/or LSD1/MAO-B.

All publications and patent applications mentioned in the specificationare indicative of the level of those skilled in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated to be incorporated by reference. The mere mentioning of thepublications and patent applications does not necessarily constitute anadmission that they are prior art to the instant application.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

The invention claimed is:
 1. A compound of Formula (I) or apharmaceutically acceptable salt or solvate thereof:

wherein: (A) is phenyl, wherein said phenyl has n substituents (R3); (B)is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclyl group orthe cyclyl moiety comprised in said (L1)-cyclyl group has n substituents(R2), and wherein said cyclyl group or the cyclyl moiety comprised insaid -(L1)-cyclyl group is a phenyl group; (L1) is —O—, —NH—,—N(alkyl)-, alkylene or heteroalkylene; (D) is a heteroaryl group or an-(L2)-heteroaryl group, wherein said heteroaryl group or the heteroarylmoiety comprised in said -(L2)-heteroaryl group is imidazolyl,pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, thiadiazolyl orfurazanyl, wherein said heteroaryl group or the heteroaryl moietycomprised in said -(L2)-heteroaryl group has one substituent (R1), andfurther wherein said heteroaryl group is covalently bonded to theremainder of the molecule through a ring carbon atom or the heteroarylmoiety comprised in said -(L2)-heteroaryl group is covalently bonded tothe (L2) moiety through a ring carbon atom; (L2) is —O—, —NH—,—N(alkyl)-, alkylene or heteroalkylene; (R1) is a hydrogen bondinggroup; each (R2) is independently selected from alkyl, alkenyl, alkynyl,cyclyl, amino, amido, C amido, alkylamino, hydroxyl, nitro, halo,haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy,acyl, carboxyl, carbamate or urea; each (R3) is independently selectedfrom alkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino,hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl,sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and n isindependently 0, 1, 2, 3 or
 4. 2. The compound of claim 1 wherein (A)has 0 substituents (R3).
 3. The compound of claim 1 wherein (B) is—O—CH₂-phenyl or phenyl, and further wherein said phenyl or the phenylmoiety comprised in said —O—CH₂-phenyl has n substituents (R2).
 4. Thecompound of claim 1 wherein (B) has 0, 1 or 2 substituents (R2).
 5. Thecompound of claim 1 wherein (D) is thiazolyl, oxadiazolyl, oxazolyl,isoxazolyl, or thiadiazolyl, and further wherein said thiazolyl, saidoxadiazolyl, said oxazolyl, said isoxazolyl, or said thiadiazolyl hasone substituent (R1).
 6. The compound of claim 1 wherein (D) isthiazolyl or oxadiazolyl, and further wherein said thiazolyl or saidoxadiazolyl has one substituent (R1).
 7. The compound of claim 1 wherein(D) is oxadiazolyl, wherein said oxadiazolyl has one substituent (R1).8. The compound of claim 1 wherein (R1) is —OH, —O(alkyl), —NH₂,—NH(alkyl), —N(alkyl)(alkyl), amido, —SO—NH₂, —SO—NH(alkyl),—SO—N(alkyl)(alkyl), —S(O)₂NH₂, —S(O)₂NH(alkyl), —S(O)₂N(alkyl)(alkyl),—C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)(alkyl), -alkylene-C(═O)NH₂,-alkylene-C(═O)NH(alkyl), -alkylene-C(═O)N(alkyl)(alkyl),—NHC(═O)-alkyl, —N(alkyl)-C(═O)-alkyl, -alkylene-NH₂,-alkylene-NH(alkyl), or -alkylene-N(alkyl)(alkyl).
 9. The compound ofclaim 1 wherein (R1) is —OH, —NH₂, amido, —S(O)₂NH₂, —C(═O)NH₂,—CH₂—C(═O)NH₂, —NHC(═O)CH₃, —NHCH₃, N(CH₃)₂ or —CH₂—NH₂.
 10. Thecompound of claim 1 wherein (R1) is —NH₂.
 11. The compound of claim 1wherein (R2) is independently selected from hydroxyl, halo or haloalkyl.12. The compound of claim 1 wherein the substituents on the cyclopropylmoiety are in trans-configuration.
 13. The compound of claim 1 whereinsaid compound is selected from:5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1oxadiazol-2-amine;5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)aminomethyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;4′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;4-((((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;or a pharmaceutically acceptable salt or solvate thereof.
 14. Thecompound of claim 1 wherein said compound is selected from:4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt or solvate thereof.
 15. Thecompound of claim 12 wherein said compound is an optically activestereoisomer.
 16. The compound of claim 12 wherein said compound is the(−) stereoisomer.
 17. The compound of claim 12 wherein said compound isthe (+) stereoisomer.
 18. The compound of claim 1 wherein said compoundis selected from: (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;(−)N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;(−)5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt or solvate thereof.
 19. Apharmaceutical composition comprising the compound of claim 1 and apharmaceutically acceptable carrier.
 20. A method of treating aneurological disease or disorder, wherein said neurological disease ordisorder is selected from depression, Alzheimer's disease, Huntingtondisease, Parkinson's disease, Amyotrophic Lateral Sclerosis,Frontotemporal Dementia, or Dementia with Lewy Bodies, the methodcomprising administering, to a subject in need of such treatment, thecompound of claim
 1. 21. The method of claim 20 wherein said compound isselected from:4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt or solvate thereof.
 22. The methodof claim 20 wherein said compound is selected from: (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-N-methyl-1,3,4-oxadiazol-2-amine;(−)N-(5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)acetamide;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;(−)5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt or solvate thereof.
 23. A methodof treating cancer, wherein said cancer is selected from prostatecancer, breast cancer, lung cancer, colorectal cancer, brain cancer,skin cancer, blood cancer, leukemia, lymphoma, or myeloma, the methodcomprising administering, to a subject in need of such treatment, thecompound of claim
 1. 24. The method of claim 23 wherein said leukemia isselected from acute myelogenous leukemia (AML), chronic myelogenousleukemia (CML), chronic neutrophilic leukemia, chronic eosinophilicleukemia, chronic lymphocytic leukemia (CLL), acute lymphoblasticleukemia (ALL), or hairy cell leukemia.
 25. A compound of Formula (I) ora pharmaceutically acceptable salt thereof:

wherein: (A) is phenyl, wherein said phenyl has n substituents (R3); (B)is a cyclyl group or an -(L1)-cyclyl group, wherein said cyclyl group orthe cyclyl moiety comprised in said -(L1)-cyclyl group has nsubstituents (R2), and wherein said cyclyl group or the cyclyl moietycomprised in said -(L1)-cyclyl group is a phenyl group; (L1) is —O—,—NH—, —N(alkyl)-, alkylene or heteroalkylene; (D) is thiazolyl,oxadiazolyl, oxazolyl, isoxazolyl, or thiadiazolyl, and further whereinsaid thiazolyl, said oxadiazolyl, said oxazolyl, said isoxazolyl, orsaid thiadiazol has one substituent (R1); (R1) is —NH₂; each (R2) isindependently selected from alkyl, alkenyl, alkynyl, cyclyl, amino,amido, C-amido, alkylamino, hydroxyl, nitro, halo, haloalkyl,haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, alkoxy, acyl,carboxyl, carbamate or urea; each (R3) is independently selected fromalkyl, alkenyl, alkynyl, cyclyl, amino, amido, C-amido, alkylamino,hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl,sulfonamide, alkoxy, acyl, carboxyl, carbamate, or urea; and n isindependently 0, 1, 2, 3 or
 4. 26. The compound of claim 25, wherein:(D) is oxadiazolyl, wherein said oxadiazolyl has one substituent (R1).27. The compound of claim 25, wherein: (B) is —O—CH₂-phenyl or phenyl,and further wherein said phenyl or the phenyl moiety comprised in said—O—CH₂-phenyl has n substituents (R2).
 28. The compound of claim 25,wherein: (B) is —O—CH₂-phenyl or phenyl, and further wherein said phenylor the phenyl moiety comprised in said —O—CH₂-phenyl has n substituents(R2); and (D) is oxadiazolyl, wherein said oxadiazolyl has onesubstituent (R1).
 29. The compound of claim 25, wherein: (B) is—O—CH₂-phenyl or phenyl; and further wherein said phenyl or the phenylmoiety comprised in said —O—CH₂-phenyl has n substituents (R2); and thesubstituents on the cyclopropyl moiety are in trans-configuration. 30.The compound of claim 25, wherein: (B) is —O—CH₂-phenyl or phenyl, andfurther wherein said phenyl or the phenyl moiety comprised in said—O—CH₂-phenyl has n substituents (R2); (C) is oxadiazolyl, wherein saidoxadiazolyl has one substituent (R1); and the substituents on thecyclopropyl moiety are in trans-configuration.
 31. The compound of claim25, wherein: (B) is —O—CH₂-phenyl, and further wherein the phenyl moietycomprised in said —O—CH₂-phenyl has n substituents (R2); (D) isoxadiazolyl, wherein said oxadiazolyl has one substituent (R1); and thesubstituents on the cyclopropyl moiety are in trans-configuration. 32.The compound of claim 25, wherein (A) has 0 substituents (R3).
 33. Thecompound of claim 31, wherein (A) has 0 substituents (R3).
 34. Thecompound of claim 25, wherein (B) has 0, 1 or 2 substituents (R2). 35.The compound of claim 31, wherein (B) has 0, 1 or 2 substituents (R2).36. The compound of claim 25, wherein (R2) is independently selectedfrom hydroxyl, halo or haloalkyl.
 37. The compound of claim 31, wherein(R2) is independently selected from hydroxyl, halo or haloalkyl.
 38. Thecompound of claim 25, wherein the substituents on the cyclopropyl moietyare in trans-configuration.
 39. The compound of claim 38, wherein saidcompound is an optically active stereoisomer.
 40. The compound of claim38, wherein said compound is the (−) stereoisomer.
 41. The compound ofclaim 38, wherein said compound is the (+) stereoisomer.
 42. Thecompound of claim 25, wherein said compound is selected from:5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)thiazol-2-amine;4′-((trans)-2-((2-aminothiazol-5-yl)methylamino)cyclopropyl)biphenyl-3-ol;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,2,4-oxadiazol-3-amine;5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((4-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((3-chlorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;4′-((trans)-2-(((5-amino-1,3,4-oxadiazol-2-yl)methyl)amino)cyclopropyl)-[1,1′biphenyl]-3-ol,5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)thiazol-5-amine;4-((((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)methyl)thiazol-2-amine;2-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)oxazol-5-amine;3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)isoxazol-5-amine;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-3-amine;3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-thiadiazol-3-amine;or a pharmaceutically acceptable salt thereof.
 43. The compound of claim25, wherein said compound is selected from: (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;(−)5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 44. The compound of claim25, wherein said compound is (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 45. The compound of claim25, wherein said compound is (−)5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine:or a pharmaceutically acceptable salt thereof.
 46. The compound of claim25, wherein said compound is (−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 47. The compound of claim25, wherein said compound is (−)5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 48. The compound of claim25, wherein said compound is5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine:or a pharmaceutically acceptable salt thereof.
 49. The compound of claim25, wherein said compound is5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 50. The compound of claim25, wherein said compound is5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 51. The compound of claim25, wherein said compound is5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,34-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 52. The compound of claim25, wherein said compound is5-((((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine,or a pharmaceutically acceptable salt thereof.
 53. The compound of claim25, wherein said compound is5-((((trans)-2-(4-((3,5-difluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 54. The compound of claim25, wherein said compound is3-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,2,4-oxadiazol-5-amine;or a pharmaceutically acceptable salt thereof.
 55. A pharmaceuticalcomposition comprising the compound of claim 25 and a pharmaceuticallyacceptable carrier.
 56. A pharmaceutical composition comprising thecompound of claim 42 and a pharmaceutically acceptable carrier.
 57. Apharmaceutical composition comprising the compound of claim 43 and apharmaceutically acceptable carrier.
 58. A method of treating aneurological disease or disorder, wherein said neurological disease ordisorder is selected from Alzheimer's disease, Huntington disease,Parkinson's disease, Amyotrophic Lateral Sclerosis, FrontotemporalDementia, or Dementia with Lewy Bodies, the method comprisingadministering, to a subject in need of such treatment, the compound ofclaim
 25. 59. The method of claim 58 wherein said compound is selectedfrom: (−)5-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;(−)5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-thiadiazol-2-amine;(−)5-((((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-amine;or a pharmaceutically acceptable salt thereof.
 60. A method of treatinga neurological disease or disorder, wherein said neurological disease ordisorder is selected from Alzheimer's disease, Huntington disease,Parkinson's disease, Amyotrophic Lateral Sclerosis, FrontotemporalDementia, or Dementia with Lewy Bodies, the method comprisingadministering, to a subject in need of such treatment, the compound ofclaim
 42. 61. A method of treating cancer, wherein said cancer isselected from prostate cancer, breast cancer, lung cancer, colorectalcancer, brain cancer, skin cancer, blood cancer, leukemia, lymphoma, ormyeloma, the method comprising administering, to a subject in need ofsuch treatment, the compound of claim
 25. 62. A method of treatingcancer, wherein said cancer is selected from prostate cancer, breastcancer, lung cancer, colorectal cancer, brain cancer, skin cancer, bloodcancer, leukemia, lymphoma, or myeloma, the method comprisingadministering, to a subject in need of such treatment, the compound ofclaim
 42. 63. A method of treating cancer, wherein said cancer isselected from prostate cancer, breast cancer, lung cancer, colorectalcancer, brain cancer, skin cancer, blood cancer, leukemia, lymphoma, ormyeloma, the method comprising administering, to a subject in need ofsuch treatment, the compound of claim 43.